extended microbiome 확장된 미생물총.. 2024년 cell 외부발효의 정의

[문형철]

이 논문은

발효식품을 단순히 “프로바이오틱스가 들어있는 음식”으로 보지 않고,

인간의 장내 미생물총(gut microbiome)을 확장하는

‘확장된 미생물총(extended microbiome)’으로 재정의한 중요한 리뷰입니다.

발효 과정에서 생성되는

인간 관련 대사산물(metabolites)과 그 생물학적 작용에 초점을 맞춥니다.

1. 핵심 개념: Extended Microbiome

장내 미생물이 무산소 환경에서 수행하는 발효(fermentation)와 식품 발효는 본질적으로 같은 과정입니다.

• 다당류와 아미노산을 분해하여 다양한 생리활성 대사산물을 만듭니다.
• 이 대사산물들은 식품의 안전성·보존성·풍미·영양 가용성을 결정하는 동시에, 섭취 후 숙주(인간)의 면역·대사·장내 미생물에 직접 신호를 보냅니다.

저자들은 발효식품을

“우리가 매일 섭취하는 외부 미생물 및 대사산물 저장소”로 보고,

이를 장내 미생물총의 연장선으로 이해해야 한다고 주장합니다.

2. 발효식품의 정의와 역사

• 정의: 미생물 성장과 효소적 변환에 의해 원재료가 변화된 식품. 자연 발효(spontaneous), starter culture 사용, back-slopping(이전 배치를 접종) 방식으로 만들어집니다.
• 주요 미생물: 젖산균(LAB: Lactobacillus, Leuconostoc, Streptococcus 등), 효모, 일부 곰팡이(Aspergillus oryzae 등).
• 역사적 배경:
  • 약 1만 4천 년 전 인류 기록부터 존재.
  • 약 1천만 년 전 이미 알코올 대사 효소(ADH4)가 진화하여 발효된 과실을 이용할 수 있었음.
  • 메치니코프(Élie Metchnikoff)가 불가리아인의 장수와 요거트를 연결하면서 현대 프로바이오틱스 개념이 탄생.

3. 주요 대사산물과 작용 기전

발효식품에서 특히 중요한 인간 관련 대사산물들입니다.

대사산물                                                  대표 식품                                주요 수용체/작용                생리적 효과

Lactate (젖산)	요거트, 김치, 사우어크라우트	GPR81	그렐린 억제, 염증 감소, 지방분해 조절
Acetate (아세트산)	콤부차, 식초	GPR41/43	PYY·GLP-1 분비 촉진, Treg·IgA 조절
D-PLA (D-phenyllactic acid)	김치, 사우어크라우트	HCA3	면역-대사 조절
SCFAs (부티레이트, 프로피오네이트 등)	다양한 발효식품	GPR41/43, HCA2	장 장벽 강화, 항염증, 인슐린 민감성
Succinate	된장, 미소	GPR91	콜라겐 합성, 염증·지방분해 조절
Aryl-lactates (4-HPLA, ILA 등)	젖산 발효식품	AhR	면역 항상성 유지
Hippuric acid, 3-3-PPA	일부 발효식품	HCA2	항염증

이 대사산물들은 소장 점막 면역계, 장내분비세포(enteroendocrine cells), 그리고 장내 미생물과 직접 상호작용합니다.

4. 건강 효과와 임상적 증거

• 장내 미생물 다양성 증가: 정기적인 발효식품 섭취는 장내 미생물 다양성을 높이고, 일부 미생물의 정착(engraftment)을 유도할 수 있습니다. (Sonnenburg 그룹의 이전 RCT에서 10주간 발효식품 섭취 시 염증 지표 감소와 다양성 증가가 관찰됨)
• 면역 조절: 염증성 사이토카인 감소, IgA 반응 촉진, Treg 세포 조절.
• 대사 질환: 제2형 당뇨병, 비만, IBD 등에서 잠재적 이점이 동물 및 일부 인체 연구에서 보고됨.
• 주의점: 일부 발효식품에서 생성되는 biogenic amines(티라민, 히스타민 등)은 민감한 사람에게 혈압 상승 등을 유발할 수 있음.

5. 미생물-미생물 상호작용과 한계

발효식품의 미생물은

장내 미생물과 경쟁·공생하며,

유기산과 bacteriocin을 통해 병원균 억제에 기여합니다.

그러나

• 배치마다 미생물 조성과 대사산물 농도가 크게 달라질 수 있고,
• 실제 섭취량과 생체이용률, 장기 효과에 대한 고품질 임상시험이 아직 부족합니다.

6. 결론 및 향후 방향

저자들은 발효식품이

1. 화학적 다양성이 매우 큰 “살아있는 기능성 식품”이며,
2. 장내 미생물총을 확장하는 현실적인 수단이고,
3. 지속가능한 식품 시스템과 개인 맞춤형 건강관리에 기여할 잠재력이 크다고 강조합니다.

필요한 연구 방향으로는

• 체계적인 대사체학(metabolomics)과 유전체 분석,
• 미생물 균주 수준의 특성화,
• 환자 대상 대규모 임상시험,
• 발효 조건 최적화를 통한 일관된 대사산물 생산을 제시합니다.

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이 논문은 “발효식품 = 프로바이오틱스”라는 단순한 프레임을 넘어서, 발효 대사산물 자체가 숙주 신호전달 경로에 직접 작용한다는 점을 체계적으로 정리한 중요한 리뷰입니다. 특히 Justin Sonnenburg와 Suzanne Devkota가 공동 저자로 참여한 만큼, 장내 미생물-숙주 상호작용 관점에서 매우 깊이 있는 시각을 제공합니다

ReviewVolume 36, Issue 4p684-701April 02, 2024Open Archive

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Our extended microbiome: The human-relevant metabolites and biology of fermented foods

Elisa B. Caffrey1 Send email to ecaffrey@stanford.edu ∙ Justin L. Sonnenburg1,2,3 Send email to justins2@stanford.edu ∙ Suzanne Devkota4,5 Send email to suzanne.devkota@cshs.org

Affiliations & Notes

Article Info

DOI: 10.1016/j.cmet.2024.03.007 External LinkAlso available on ScienceDirect External Link

Copyright: © 2024 Elsevier Inc. All rights reserved.

User License: Elsevier user license | Elsevier's open access license policy

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Summary

One of the key modes of microbial metabolism occurring in the gut microbiome is fermentation. This energy-yielding process transforms common macromolecules like polysaccharides and amino acids into a wide variety of chemicals, many of which are relevant to microbe-microbe and microbe-host interactions. Analogous transformations occur during the production of fermented foods, resulting in an abundance of bioactive metabolites. In foods, the products of fermentation can influence food safety and preservation, nutrient availability, and palatability and, once consumed, may impact immune and metabolic status, disease expression‎, and severity. Human signaling pathways perceive and respond to many of the currently known fermented food metabolites, though expansive chemical novelty remains to be defined. Here we discuss several aspects of fermented food-associated microbes and metabolites, including a condensed history, current understanding of their interactions with hosts and host-resident microbes, connections with commercial probiotics, and opportunities for future research on human health and disease and food sustainability.

Keywords

1. fermentation
2. fermented foods
3. metabolomics
4. gut microbiome
5. microbial metabolites

Introduction

In food, fermentation includes “foods made through desired microbial growth and enzymatic conversions of food components,”1 occurring in aerobic and anaerobic contexts. The food fermentation process (see “What are fermented foods?” section) depends upon the microbial community to metabolize nutrients,2 altering the substrate (i.e., food) and producing metabolites and other molecules that can impact taste, texture, safety, and nutritional composition, as well as signal to the host and gut microbiome.

While this type of food fermentation happens ex vivo, a comparable microbial metabolism occurs in the gastrointestinal (GI) tract. Research on the gut microbiome has highlighted the importance of microbiome-derived metabolites in mediating human health and disease.3,4,5,6,7,8,9 By applying the same framework developed to study metabolite-host interactions in the gut, we can better understand the effects of fermented food metabolism on human health, offering an unexplored additional source of human-relevant microbial metabolites. From the perspective of the gut microbiome, fermentation can be defined as a primary metabolic process occurring in the absence of oxygen, such as the microbial consumption of complex carbohydrates in the colon. Dietary compounds metabolized by the gut microbiome lead to production of energy and metabolites, small chemical compounds that can influence the structure of gut microbial communities and signal directly to the host via interaction with different cell types within the gut10,11 or signal peripherally following absorption into circulation. Nutrients exiting the stomach that are not absorbed by the host small intestine make their way to the distal small intestine and colon, providing a pool of dietary compounds that gut microbes can access and metabolize.

Microbial strains that are well-matched to incoming nutrients tend to outcompete other members of the community, resulting in changes in the overall composition of the microbial community.12,13 This can occur within days of a major dietary change.14 The metabolites produced during microbial fermentation in the gut are a direct product of microbes that are being fueled by nutrient inputs. These compounds provide an energy source for other microbes; impact the ecosystem chemistry (e.g., pH); directly signal to the host, further restructuring the microbial community; and/or enter host systemic circulation, broadening metabolite reach.10,15,16,17 Postbiotics refer to the molecules that microbes produce18 as opposed to substrates that promote the growth of gut microbes, known as prebiotics. In this framework, diet can be considered a source of nutrients for both host and microbes, as well as a source of precursors for metabolites produced during fermentation by the gut microbiome.

There is a growing appreciation that microbially produced metabolites have a mediating role in health and disease, as seen in type 2 diabetes (T2DM), inflammatory bowel diseases (IBDs), and metabolic-associated fatty liver disease.3,4,5,6,7,8,9 Evidence of the influence of microbial-derived metabolites primarily comes from mechanistic studies, where they may promote health and disease states, as well as in their use as diagnostics or biomarkers. Production of these metabolites is influenced by a vast array of factors including diet, medications, baseline gut microbiota composition, and genetics.19 Similarly, metabolites produced during food fermentation offer a novel pool of signaling compounds that can interact with the GI tract, acting directly and indirectly on the host, with the potential to be further metabolized.

Consumption of fermented foods expands the possible interactions in the gut through increased chemical diversity. By considering food fermentation as an “extended microbiome,”20 a term previously used to describe fermented foods by Dunn et al.,20 we can reframe our relationship to fermented foods and their role in human health. Important considerations include how the practice of fermentation has shaped human biology, how fermented food consumption impacts health directly and indirectly, and future applications of food fermentation in biomedicine and extending beyond health. This review focuses on the role of metabolites as key mediators in the diet-microbe-host landscape, presenting current and potential roles fermented food microbiota-derived metabolites play in human health. We also review the need for expanded foundational information, such as characterizing the microbial communities and molecules associated with the wide array of fermented foods consumed globally.

What are fermented foods?

With the fermented food market expected to grow by over half a billion dollars in the next 4 years,21 fermentation has been of increasing research interest. Numerous reviews have offered an extended explanation of fermented food production.1,2 Here, we offer a brief summary.

Fermented foods (also referred to as ferments or microbial foods) are foods transformed by microbial growth and enzymatic conversions.1 During fermentation, members of the microbial community, which can include bacteria, yeast, or filamentous fungi, compete for resources with strain-specific nutritional and growth-condition preferences, accompanied by secretion of metabolites such as organic acids and antimicrobial peptides22,23 to gain advantage over competitors. Most fermented food is produced for specific sensory qualities including taste and aroma, which result from the production of specific metabolites. Key to the fermentation process is encouraging the growth of microbes through the manipulation of extrinsic factors such as temperature, pH, salinity, and humidity.

Where are the microbes coming from?

The source of microbes in a fermented food can be spontaneous, from a starter culture, or through “back-slopping.” In spontaneous fermentation, microbes from the environment (e.g., the surface of the raw ingredient, the hands of the producer, the room, and the equipment used to make the fermented food) initiate fermentation.24 While the initial microbial community will be more diverse, the raw ingredient and environmental factors will select for specific members of the community to dominate.25 Use of a starter culture (e.g., selected strain or group of strains) in a pasteurized substrate allows for a reliable final profile of the fermented food, preventing competition between the native microbial community and the added starter community. Starter cultures are widely used in fermented dairy production like yogurt and cheeses.20 In addition, starters can be constructed of characterized and sequenced strains deliberately chosen based on the presence or absence of specific traits, for example, to minimize the presence of antibiotic resistance genes that might be transferable to resident gut microbes.26 When a portion of a previous fermented food is incorporated into a next batch, propagating the microbial community, the process is called back-slopping fermentation2 and is analogous to subculturing or serial passage of microbial cultures in the lab. Examples of back-slopping include sourdough bread and kombucha,2,27 where a higher abundance of a previously successful microbial community can be used to initiate fermentation, although the community itself might be poorly characterized.

Dominant microbes involved in fermentation have been largely characterized, but there remains a need for the continued characterization of microbes involved in fermentation: in particular, characterization of microbes at lower abundance, which might play a role in shaping the microbial community or contribute to the metabolite pool. In addition, while there is general consistency in microbes that will be most abundant at the final stages of fermentation, like Lactiplantibacillus plantarum in vegetable fermentation or S. thermophilus and L. bulgaricus in yogurt, their final relative abundance, as well as the presence and abundance of other microbes in the community, remain variable from batch to batch. In line with microbial heterogeneity between fermentation batches, metabolite production and abundance will also be variable.28 Ongoing work modeling microbiota and metabolite dynamics during fermented food community assembly will shed light on how extrinsic factors might be used to decrease product variability.24

What does it mean for a food to be fermented?

While there are broad categories of microbes that can be involved in the fermentation process (e.g., lactic acid bacteria, acetic acid bacteria, filamentous molds, and yeast), lactic acid fermenting microbes are one of the most common classes, seen in the fermentation of many vegetables, dairy, and grains (e.g., kimchi, yogurt, and injera). In lactic acid fermentation of vegetables, addition of salt and access to preferred carbohydrate nutrient sources promote growth of halophilic lactic acid bacteria (LAB), leading to early community dominance and secretion of antimicrobial peptides and organic acids (predominantly lactic acid), further enhancing growth.29,30,31 LAB outcompetes potential spoilage-associated microbes and competitors, excluding undesirable microbes from the final ferment. Secretion of protein hydrolases to enhance nutrient accessibility, shown primarily in mold fermentation microbes like Aspergillus oryzae and Rhizopus oryzae, not only promotes fungal growth but also plays an important role in enhanced palatability of the fermented food. Additional metabolites produced during this process play important roles in enhancing palatability and food safety and mediate microbe-microbe and microbe-host interactions. It is important to note that many non-fermented foods are produced to mimic the flavor and preservation of fermented foods (e.g., vinegar/salt brined pickles).1 Manufacturers may add viable microbes to pickled foods or pasteurized fermented foods at the end of production, attempting to recreate the living microbial content of raw fermented foods and enabling “probiotic” or “contains live microbes” label claims; in many cases the supplemented microbes are different strains than those associated with fermentation and may be spores and therefore not metabolically active. Microbial density of lactic acid ferments ranges widely across products and can reach 105–1010 CFU/g32 with the microbes producing and consuming metabolites during microbial growth. While addition of probiotic microbes to consumer-ready food products increases CFU count, fermentation (and the accompanying metabolite production) does not occur. Therefore, the simple presence of bacteria or fungi on an ingredient label does not necessarily mean it is a fermented product. For example, an olive brined in dilute lactic acid and salt with spores of a Bacillus species (distant relative of Lactobacillus that is able to form spores) added before sealing can create a shelf-stable product with highly reproducible flavor that mimics a lactic acid ferment and enables a claim of “contains live microbes.” However, such a product deviates significantly from a traditionally fermented olive. Data are lacking as to whether mimicking food fermentation by adding purified metabolites or live microbes has the same benefit, particularly when consuming microbes distinct from those that are typically found in fermented foods. Also, in the addition of probiotics (considered "dietary supplements") to food FDA draft guidelines recommend including the total weight of the added microbial mass and CFU of viable microbes, with no recommendation as to maximum allowed supplemented probiotic CFU or weight count.33 While estimates from the National Health and Nutrition Examination Survey (NHANES) data show there is a trending increase in consumption of foods containing live microbes in the American diet, estimates of CFUs or microbial type are still lacking.34 Characterizing the typical range of dietary microbe consumption and defining a healthy personalized range is necessary for the establishment of dietary recommendations and regulation of commercial products.35

Fermented foods: A brief history

While the earliest evidence of human engagement with food fermentation dates back to at least 14,000 years BCE,36 evolutionary genetics support a much longer relationship between humans and food-derived microbially produced metabolites. Roughly 10 million years ago, corresponding to the movement of our great ape ancestors from trees to the forest floor, evolution of the alcohol dehydrogenase class IV (ADH4) enzyme allowed our hominid ancestors to metabolize ethanol, likely a primary metabolite produced by yeast spontaneously fermenting fallen fruit.37 Over the course of human history, food fermentation has been practiced by most culinary traditions, dependent on substrate availability.20 The use of fermented ingredients is not uncommon in historical medicinal practices, with documented use of wine, doenjang (Korean fermented soybean paste), and garum (fermented fish sauce)38,39,40 for the treatment and prevention of ailments. The modern conceptualization of microbial foods as “health foods” stems from Élie Metchnikoff, who hypothesized Bacillus bulgarian (now Lactobacillus delbrueckii subsp. bulgaricus), which had been isolated from Bulgarian curdled milk referred to as “yahourth,” was responsible for the increased longevity observed in the Balkan population compared to other European populations. Work on the isolation and administration of this strain established probiotics as both a concept and a commercial product (Box 1). A revitalization of at-home fermentation production41 accompanied by the rise in the commercial fermented food market21 has focused on marketing fermented foods for “health” properties, although there is a lack of consensus on how and in what context health can be defined.35 Here we present the current understanding and limitation of the use of microbial foods for human health, focusing on the role of metabolites as microbe-host mediators and highlighting areas of future research.

Box 1

Fermented foods and probiotics

L. delbrueckii subsp. bulgaricus is one of the key starter strains used to make yogurt today42 and was also the first described probiotic,43 isolated from fermented dairy. The term probiotic refers to a well-defined and characterized live microorganism with demonstrated health benefits,1 which might be consumed in pure form (e.g., probiotic pill) or added to a food (e.g., probiotic yogurt). According to this definition, fermented foods made with spontaneous fermentation or through back-slopping do not fit the formal definition of probiotic unless the microbiome of the fermented food has been characterized and the strains are proven to exert health benefits. In commercial fermented food preparation, probiotic strains might be added into the yogurt once fermentation is complete, as with L. plantarum and L. rhamnosus,44 two strains also found in fermented foods,45 or many of the Bifidobacterium spp. strains that are not associated with food fermentation but rather were isolated from other sources such as infant feces.46,47

While probiotics have been extensively reviewed,48 success in trials is highly variable and appears dependent on a number of factors. A randomized, double-blind, placebo-controlled study looking at the impact of stomach acid on probiotic intervention showed that suppression of stomach acid production with proton pump inhibitors (PPIs) might enhance probiotic effectiveness, possibly via improved viability.49 More recently, a randomized controlled trial looking at the effects of probiotics on metabolic syndrome identified diet as a key differentiating factor between responders and non-responders, with non-responders having higher levels of serum glucose and insulin at the end of the intervention.50 Unexpectedly, total and added sugar, lactose, and sucrose intake was higher in the probiotic responders compared to non-responders. Further research is needed to better understand basic interactions between probiotics, diet, host gut microbiome, and host.

Current research points to metabolites and other probiotic products (sometimes commercially referred to as “postbiotics”) as key contributors to many of the benefits seen by probiotic consumption.18,51 While probiotics offer a characterized bacteria for a specific indication, in supplement form these products lack fermentation end products. Alternatively, fermented foods offer an extensive reservoir of potential postbiotics that can directly impact the microbiome, immunity, and enteroendocrine system.

The extended microbiome

Metabolites produced during fermentation provide a key role in the increased safety,52 nutrient availability,53,54,55,56,57,58,59,60,61,62,63,64 and enhanced gustatory qualities22,65,66 of fermented foods. Understanding how the microbial strains present combined with other factors, including salinity, pH, and temperature, contribute and influence metabolite production remains a necessary consideration when characterizing the final fermented product, particularly when it comes to food safety.

Enhancing food safety

Preserving food through fermentation is a reliable technique to enhance safety and stability over a prolonged period of time. During fermentation, metabolites produced during microbial competition for nutrients inhibit growth of competitors, concomitantly preventing growth of potential human pathogens. Production of various organic acids, primarily lactic or acetic acid, decrease the pH and create an inhospitable environment for food-borne pathogens like C. botulinum, L. monocytogenes, E. coli O157:H7, and S. flexneri.67,68,69 Secretion of antimicrobial compounds like bacteriocins, antibacterial peptides with both narrow and broad-spectrum activity, has been extensively studied in fermented food-associated LAB, including in kimchi, cheese, and fermented cereals,23,29,70,71 and shows high specific activity against known food pathogens.29 To date in the US, no cases of botulism have been reported in vegetable fermentation, mold-based fermentation, or dairy fermentation,72 with the rare cases being home-fermented meats, including beaver tail and uneviscerated fish, and tofu.73

Much of the insight into the mechanisms underlying the ecology of fermented foods has come from their use as a model microbial ecosystem. One example is the identification of novel antimicrobials that mediated microbe-microbe interactions,25,74,75 highlighting fermented foods as a potentially rich source of novel antimicrobials for medical application. More generally, the reduced microbial diversity in fermented foods compared to the gut microbiome provides improved tractability for exploring community assembly, transkingdom interactions, strain-diversity, and microbial evolution.76

Fermentation can also enhance food detoxification. Raw cassava, a starchy tuberous root native to South America and a staple food for over 500 million people,77 contains high levels of neurotoxic cyanogenic glycosides,78 which can be reduced by >70% through fermentation,79 with L. plantarum and Loigolactobacillus coryniformis believed to play a major role.80,81 Consumption of unprocessed cassava can lead to development of the irreversible neurological disorder konzo, which disproportionately affects rural areas in Africa.82 Gaining mechanistic insight into cassava detoxification would allow for improvement in food safety, with potential application to other foods.

Increasing nutrient availability and antioxidants

Fermented foods also have a documented history of use as nutrient supplements. James Cook, the British explorer, successfully prevented and treated scurvy among his crew by instructing them to consume 2 lb. of sauerkraut each a week, estimated to provide about 150 mg of ascorbic acid.53 However, these increased concentrations in nutrients might be specific to the microbial strains found in the ferment. Early work looking at prevention of scurvy in guinea pigs fed commercial sauerkraut found that two of the sauerkrauts successfully prevented scurvy while two other sauerkrauts did not. No difference was identified between the sauerkraut manufacturing conditions; however, microbial communities that might be involved in the observed differences were not investigated for potential differences.54 More recent studies support an increase in vitamins and nutrients in fermented foods compared to unfermented ingredients, including vitamins C, B2, B12, and K and folate.55,56,57,58,59,60,83 Additionally, release of encrypted bioactive components like polyphenol and flavonoid from tea leaves over the course of kombucha production increases antioxidant content of the drink.61 There is some rodent evidence pointing to host benefits following consumption of fermentation-driven enhanced nutrient bioavailability62,63; however, the chemical complexity combined with depletion of precursors (e.g., glucose) provides many confounders. Additional work is needed to isolate the effects of the wide array of relevant variables such as (1) diversity and variability in nutrients across fermented food; (2) the fermented food microbiota at a strain-specific level; and (3) elucidating factors, including host and microbiome genetics, that can impact nutrient absorption.

Flavor and taste

Fermentation is often practiced for its culinary use, where transformation of taste, smell, texture, and other sensory stimuli of the food during this metabolic process acts in synthesis to change the perceived flavor of the food. Spoilage is often associated with “off-flavors,” while novel flavors not typically associated with the starting ingredient are often a desired result of the fermentation process. For example, carbohydrate fermentation can result in the production of thiazoles and furfural, associated with nutty and almond-like flavors84,85 via sugar degradation and Maillard reaction pathways. Promotion of the Ehrlich pathway, an amino acid catabolic process, during fermentation can also lead to an increase in sulfur-containing, aromatic, and branched-chain volatiles like 2-phenylethanol, associated with a rose-like odor.30,86 Other metabolites like organic acids, flavonoids, and polyphenols can also contribute to the change in flavor of the final ferment.22,65 In addition, filamentous fungi can secrete hydrolases during fermentation,87 increasing simple amino acids and oligosaccharides and thus promoting umami and sweet taste sensation.

As expression‎ of sweet, bitter, and umami sensors is not limited to the oral cavity but expressed across the human GI tract,88 metabolites typically associated with flavor may play a role beyond the host gustatory system, particularly when coupled with nutrient absorption. Sensing of sweetness by T1R2/T1R3, a G protein-coupled receptor (GPCR) heterodimer expressed in enteroendocrine cells (EECs) in the human gut, can promote secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2).89,90,91 Activation of T1R2/T1R3 is not limited to sucrose but includes a variety of sweet-tasting stimuli including fructose and lactose, sweet amino acids such as glycine and d-tryptophan, sweet proteins such as monellin and thaumatin, and synthetic sweeteners such as aspartame and sucralose. Whether these ligands promote the same downstream T1R2/T1R3-mediated effects remains to be explored.92 Similarly, the GPCR T1R1/T1R3 mediates umami taste perception in the gut. The heterodimer is activated by L-amino acids such as monosodium glutamate (MSG; sodium L-glutamate) or L-cysteine and potentiated by inosine 5′-monophosphate (IMP) and other nucleotides. Activation of T1R1/T1R3 by MSG initiates peristaltic reflexes in rodent models, along with secretion of the pain-mediating neurotransmitter CGRP (calcitonin gene-related peptide) in the colon.93 CGRP receptor antagonists and anti-CGRP ligand monoclonal antibodies have more recently been approved for treatment and prevention of migraines.94

In humans, bitter taste perception is mediated by 25 putative members of the TAS2R (taste 2 receptor) GPCR family. Use of the bitterant caffeine has been shown to promote gastric acid secretion in the stomach through the TAS2R43 receptor,95 as well as lead to gut-derived serotonin secretion. Matured hop bitter acids (MHBAs), often added in the production of beer, have been shown to increase production of cholecystokinin (CCK) production by EECs,96 which plays a role in anorexigenic signaling and gastric emptying.97 Interestingly, olfactory receptors (ORs), a class of GPCRs typically found in the olfactory mucosa, have also been identified in the human gut. In purified form, the aromatic compound citronellal, also a volatile product of yeast geraniol fermentation in beer and wine production98,99,100 with an intense lemon scent, has been shown to stimulate GLP-1 secretion in both a human EEC line and mouse tissue across the small intestine.101 These examples illustrate the ability of molecules that trigger taste perception to impact host physiology. With growing interest in fermentation as a source of novel flavors,66 flavor-associated metabolites could impact important biological processes such as secretion of gut-derived peptides. Greater mechanistic insight into the roles metabolites produced during fermentation play both in perception of flavor and host biology is an exciting area for exploration, particularly focusing on how flavor-associated metabolites can modulate EECs (discussed later). In addition, inclusion of taste-preference and taste-perception surveys when conducting clinical fermented food research would aid in translatability and facilitate broader research into taste-associated compounds in food fermentation.

Food fermentation: Metabolite-host interactions

Consumption of a fermented food includes potential benefits beyond increased nutrient availability and food safety.58,64,45 In the gut, microbiome-derived metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids signal to the host through a variety of receptors, including transcription factors and GPCRs, playing a role in host incretin secretion, energy expenditure, and immune response.102,103,104,105,106 Insight into metabolite production in fermented foods will allow us to map similar metabolite-GPCR interactions, allowing deeper understanding of the role fermented food-associated microbes play in the host.

Metabolites and intestinal receptors

Gut microbiota-derived nicotinic acid,107 butyrate, and β-hydroxybutyrate produced in a ketoacidosis state108 can activate the hydroxycarboxylic acid receptor 2 (HCA2), expressed in a number of cell types, including the gut epithelium.109 Activation has been shown to have downstream anti-inflammatory effects,110,111 while chronic inflammation has been shown to downregulate HCA2 expression‎.112,113 HCA2 activation has also been shown to play a role in increasing bone density in weanling mice114 and suppresses NF-κB activation in colonic cell lines and in mouse colonic tissue.109 Additional metabolites, including hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3−PPA), activate HCA2.107 HA and 3-3−PPA are both products of hydroxycinnamate reduction in L. plantarum,115 commonly found in vegetable fermentation. While GPCRs are expressed across multiple cell and tissue types, their expression‎ on immune and EECs makes them of particular interest in understanding metabolite-host interaction in metabolic and immune disorders.

One of the indications of this fermented food metabolite-host relationship is the hydroxycarboxylic acid receptor 3 (HCA3). Described by Peters et al.,116 while most mammals express HCA1 and HCA2, only great apes (including humans) and siamang have an active HCA3, with humans exhibiting strongest activation. D-phenyllactic acid (D-PLA) is the only known HCA3 ligand117,118 and is produced by LAB. Measured in high concentrations in sauerkraut and up to 12.0–21.1 μg/mL in kimchi,119 it is elevated in the plasma following sauerkraut consumption.116 Lack of adequate animal models and currently no known HCA3 inhibitor has remained a challenge to the understanding of the biological relevance of HCA3.120 However, HCA3 expression‎ in human innate immune cells and adipose tissue lends to the hypothesis that HCA3 activation plays a role in host immuno-metabolism and energy storage.116 The extent to which consumption of other lactic acid-based ferments (including yogurt) can activate this receptor remains to be explored.28 Examining the effects of two primary fermented food metabolites, lactic and acetic acid, provides insight into how food fermentation can impact the host immune system. When produced by the host or gut microbiota, lactic acid activation of macrophage GPR81 reduces inflammatory responses in the colon.121,122 Oral administration of lactic acid increases microbiota-dependent regulatory T cells in the small intestine, promoting immune tolerance.123 Gut microbiota-derived acetate increases colonic IgA production and alters the capacity of the IgA pool to bind to specific members of the microbial community.124 Effects of dietary acetate have been primarily studied in disease models (Figure 1). The role of dietary acetate in healthy models remains an open area of investigation, with open questions similar to lactic acid. For both lactic and acetic acid, there is a need to (1) define the variability in organic acid production by microbial community and fermentation time point, (2) characterize the bioavailability of organic acids based on substrate type (sauerkraut compared to yogurt), and (3) gain further mechanistic insight into the downstream impact of organic acid consumption based on dosage and location of the metabolite-receptor interaction.

Figure 1 Fermented food microbes and metabolites can influence the immune system, endocrine system, and host gut microbiome

Show full captionFigure viewer

Additional metabolites previously identified in fermented foods, including the host immune-modulating metabolite D-PLA, have been shown to reach μM plasma concentrations following ingestion of sauerkraut.116 A randomized human dietary intervention showed consumption of fermented foods leads to decreased markers of inflammation140 while promoting increased gut microbiome diversity when compared to a high-fiber-consuming cohort. In this study, specific serum metabolites, which may be derived from diet, microbiome, or host (or combinations thereof), correlated with specific aspects of the immune response. Expanded understanding of fermented food metabolites, their absorption, and interaction with human biology is the next step in characterizing ferment-immune interplay (Figure 2).

Figure 2 Metabolic paradigms of fermented food-derived metabolites

Show full captionFigure viewer

EECs are hormone-producing cells accounting for about 1% of the gut epithelium. Acting at the interface between luminal content and host signaling, EECs produce more than 20 hormones in response to nutrient absorption. These hormones can signal systemically to the pancreas as well as the brain via vagal afferent neurons.175 While EECs can be stimulated directly by nutrients consumed, colonic EECs are also activated by bacterial SCFAs, notably butyrate and propionate, resulting from fiber fermentation. EEC-type distribution changes across the GI tract, with hormones like ghrelin and GIP primarily found in the upper small intestine and GLP-1 and peptide YY (PYY) primarily found in the colon,16 resulting in region-specific effects.129,176,177,178 Specific changes in gut colonization status, such as the absence of a microbiota (germ-free mice) or administration of a probiotic (Limosilactobacillus reuteri), have shown to increase GLP-1 levels, highlighting a role for microbial signaling in incretin regulations (reviewed in Arora et al.178). Recently, Akkermansia muciniphila has been shown to secrete a GLP-1-inducing metabolite, resulting in a reduction of a high-fat-diet-induced metabolic defects in mice.179 In conventional mice, PYY-positive EEC numbers increase in the colon in the presence of SCFAs via an FFA2-dependent pathway, reflected by an increase in circulating PYY, an enteroendocrine anorectic hormone.180 In humans, a study in individuals with diabetes consuming fermentable fibers for 84 days, with hemoglobin A1c (HbA1c) as primary endpoint, showed that those in the fiber arm resulted in significant reduction of HbA1c and fasting blood glucose at the end of the study. The authors found this was due to an increase in butyrate-producing bacteria and measured increases in butyrate levels resulting in significantly increased blood levels of GLP-1 and PYY over time.181 Another human study found that direct delivery of the SCFA propionate bound to inulin successfully delivered the propionate to the colon, resulting in significantly increased PYY and GLP-1 240 min after consumption of the oral propionate. Six months of daily supplementation resulted in attenuated weight gain and reduced intrahepatic lipids.182 Just as metabolites produced by the gut microbiota can influence host biology, metabolites produced during food fermentation can have similar interactions. The diversity of metabolites, many of which are likely to be distinct from those produced by gut-resident microbes, and interactions with microbes and host receptors in the small intestine likely produce an array of biological effects remain to be defined.

Ghrelin-secreting EECs also express GPR81, where lactate binding inhibits secretion of this “hunger hormone.”146 Unlike GLP-1-producing cells, which are primarily located in the colon, ghrelin-producing cells are primarily located in the stomach and duodenum, where they are more likely to interact with fermented food-derived lactic acid, with downstream effects on hunger signaling and metabolism. Additionally, mapping fermented food metabolites to GPCR receptors, particularly the number of orphan GPCRs,183 would allow for potential identification of novel GPCR-ligand pairings, expanding the development of a mechanistic framework of microbe-host interactions2 and allowing for a targeted exploration of downstream effects.

Fermented foods in human disease

The rise in health claims about fermented foods is not matched by an increase in clinical evidence. The few current studies are primarily focused on assessing the impact of fermented food on healthy individuals,23,140 with few studies looking at the role of fermented foods in patients with health conditions. Early data from irritable bowel syndrome (IBS)184,185 and metabolic diseases186,187,188,189 (including T2DM and obesity) offer examples of how fermented foods can improve human health through altering nutrient accessibility and impacting the human microbiome. These positive outcomes highlight the need for a greater understanding of the fermented food metabolome landscape to pursue molecular mechanistic mediators.

Meta-analyses of observational studies support a role of fermented dairy intake for the decreased risk of T2DM and cardiovascular disease.186,187,188,189 However, human clinical trials looking at the risk and prevention of these diseases in the context of fermented food consumption are lacking, with the strongest current evidence coming from animal models.190 A recent study on yogurt consumption in obese mouse models identified branched-chain hydroxy acids (BCHAs) produced during LAB-driven yogurt fermentation can supplement host BCHAs and improve metabolic parameters, including improved glucose tolerance and resistance to high-fat, high-sucrose diet-induced obesity. The effects appear to be driven by production of three hyodeoxycholic acids, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, and alpha-hydroxyisovalerate, produced by the gut microbiome.191

Kimchi consumption has also been studied for its impact on health, but few clinical trials have looked at the impact of consumption on metabolic disease. A small crossover clinical trial in obese patients reported significant decreases in body fat and improved metabolic markers.192 A follow-up crossover clinical trial followed prediabetic participants over the course of a 16-week period, reporting a decrease in insulin resistance and increased insulin sensitivity during the period of 10-day fermented kimchi consumption compared to 1-day fermented (defined as “fresh”) kimchi.193 Insight into how fermentation-derived metabolites impact secretion of incretin hormones like GLP-1 is an important step in understanding the mechanistic implications of fermented food consumption. Incorporating measurements of the foods’ differences in chemical composition, patient incretin hormones, insulin, and blood glucose in future clinical trials would greatly aid the understanding and translatability of laboratory work on fermented food metabolite-induced responses. There remains a clear need for randomized human clinical trials and mechanistic interrogation into how the fermented food microbiome and its metabolites interact with the host, including the resident microbial landscape.

While exploring fermented foods for health benefits remains an exciting frontier, there are examples where metabolites produced during fermentation can lead to negative health consequences in sensitive health populations. Biogenic amines are amino acid derivatives produced during fermentation that can include tyramine, histamine, cadaverine, and putrescine, with tyramine and histamine being of particular interest. Even small amounts of dietary tyramine (8–10 mg) can lead to hypertensive episodes in the presence of the antidepressant class monoamine oxidase inhibitors,194 with occasional fatalities reported.195 Dietary tyramine is increased in ferments like fish sauce, sauerkraut, and aged cheeses, but abundance can vary widely depending on food and fermentation time196; thus, patient dietary recommendations need to consider sensitivity, food type, serving size, and drug interactions. While tyramine production is enhanced by increased sodium content in the ferment, a variety of approaches have been applied to limit tyramine production during fermentation. For example, successful tyramine reduction was achieved with the addition of tyramine- or tyrosine-oxidizing LAB in a micro-cheese model.197 Similarly, certain LAB associated with food fermentation have been described as histamine producers, including Lentilactobacillus parabuchneri, Lentilactobacillus buchneri, and Oenococcus oeni,198,199,200,201 primarily with proteinaceous substrates like in dairy and meat ferments. While recommendations for a low-histamine diet show high efficacy for histamine hypersensitivity, fermented foods show a wide range of histamine abundance, with length of fermentation time, storage, and cooking method all influencing histamine abundance at ingestion.202 Mechanistic understanding of histamine production, characterization of extrinsic factors impacting production, and rapid biogenic amine detection methods are all necessary both from a clinical and a consumer perspective. It is likely that extending such detection methods to other biomolecules will aid in quality control and inform health claims, particularly as potential benefits of fermented foods on other physiological aspects are explored further.

Previous studies have shown associations of fermented food or pickled vegetable (terms used interchangeably in the studies; see “What are fermented foods section”) intake and esophageal and stomach cancer.203,204,205,206

These concerns are related to retrospective studies where the quality and contamination of the fermented foods was not tested, and many confounders exist. For example, one widely cited study published in 1980 focused on the preval‎ence of esophageal cancer in Northern Chinese populations,203 with data from 1959 to 1970. The study found a positive correlation between “pickled vegetable” consumption (likely fermented based on literature description) and esophageal cancer risk, but due to long fermentation storage period, the authors note that much of the food became covered with a white mold. This association was also seen in regions with higher consumption of laozao, a fermented sweet grain dish. However, samples were found to have high fungal contamination, including Aspergillus flavus, associated with increased production of carcinogenic compounds.207,208,209,210,211 In addition, enzymatic activity of other molds in the sample is hypothesized to allow for synthesis of N-nitroso compounds, associated with higher cancer risk.212,213 With the exception of dairy fermented products that are primarily produced using well-defined cultures, vegetable ferments and kombuchas are largely driven by spontaneous fermentation or uncharacterized microbial communities, respectively. However, fermented food found at grocery stores is required to meet hazard analysis critical control point (HACCP) compliance and go through rigorous safety testing before being commercially available, significantly decreasing the risk of contamination by toxin-producing microbes. Conversely, several studies have shown fermented food intake is associated with no increased risk or a decreased risk from certain cancers and diabetes.186,188,189,214,215,216,217,218 Future prospective studies with better characterization and documentation of types of fermented foods consumed are required to understand if such concerns are valid.

Food fermentation: Microbe-microbe interactions

Composition of an individual’s gut microbiome is influenced by host genetics and lifestyle, including diet, medical practices, and environment. Studies comparing gut microbial composition across different lifestyles note decreasing gut microbiome diversity in industrialized populations, believed to be driven by factors associated with an industrialized lifestyle including antibiotic overuse, high-fat and high-sugar diet, and decreases in breastfeeding.219 Not only does immigration to an industrialized environment from a non-industrialized environment lead to a decrease in microbial diversity,220 but this decrease in microbial diversity compounds over time and over the course of generations.219,220,221,222 Within industrialized populations, more diverse gut microbiomes are a conserved metric associated with resistance to Western-associated diseases, such as T2DM, heart disease, and colorectal cancer.223,224,225 Understanding how diet can increase an individual’s microbiome diversity is an active topic of research in the gut microbiome field. Fermented food consumption appears to be a promising tool in gut microbiome reconstruction.

Fermented foods and the human gut microbiome

Dietary nutrients and host-derived metabolites, including lactate and 3-hydroxybutyric acid, can impact the human gut microbiome, shifting microbial composition with downstream implications for host health from metabolic disease to immune status.13,19,177 Similarly, fermented food consumption appears to have important effects on the gut microbiome. The American Gut Project, a citizen science project, reported subtle but significant shifts in the beta-diversity and taxa of fermented food consumers compared to non-consumers across 6,811 participants. Of interest, fermented food consumers had an increase in conjugated linoleic acid (CLA) producers and fecal CLA,226 fatty acid metabolites that activate the nuclear receptor PPAR-γ227,228 to exert beneficial health effects on a number of conditions including IBD and T2DM.

A randomized clinical trial comparing high fermented food consumption to high fiber consumption showed fermented food consumption increased gut microbiome diversity compared to baseline, with alterations in the gut microbiome composition that were durable beyond the trial period.140 Nine amplicon sequence variants (ASVs) in the Firmicutes phylum increased across high fermented food compared to high fiber, including four members of the Lachnospiraceae family, two Ruminococcaceae, and one Streptococcaceae. This increase in gut microbiome diversity was not observed in the fiber-consuming groups. This trend in increased microbiome diversity has been further supported by a more recent randomized control trial comparing gut microbial composition following 6 weeks of fermented vegetables, pickled vegetables, or no vegetables.229 Not only was there an increase in gut microbiota diversity from baseline to completion of the study in the fermented vegetable group, but microbiota diversity did not change in the pickled vegetable or non-vegetable consumer group. Remaining questions include whether this increased diversity is mediated via host immune effects, live microbes in the fermented foods, metabolites alone, or other macromolecules and how durable the response is after cessation of fermented food consumption.

Interestingly, the majority of microbes responsible for the increase in diversity were not from the ferments and were likely either acquired from the environment or present in the hosts before the intervention but below detection limits. Whether fermented foods may act as a source of microbes to increase diversity or lead to compositional shifts that promote incorporation of transient microbes remains to be understood. Very few studies have assessed human microbiota composition before, during, and after fermented food consumption.140,229 A study comparing mother-infant strain sharing in a rural Ethiopian cohort identified two microbes from injera (Fructilactobacillus sanfranciscensis and Lactiplantibacillus xiangfangensis), a locally produced teff flour ferment, as contributors to diversity in maternal-infant cohorts.230 However, due to the popularity of injera consumption, whether these microbes were transient or had become incorporated into the gut microbiome could not be determined.

Comparison of LAB genomes from fermented foods to the human microbiome reveals distinct sequences, supporting the idea that fermented foods are a transient source of LAB for the gut microbiome. Differences in LAB species identified across Western and non-Western gut microbiome populations appear to reflect lifestyle.231 Understanding which LABs are transient or engrafted stable members of the gut community should be aided by more investigation and improved genomic resolution. Early work on engraftment into the gut microbial community shows successful incorporation of microbes is largely dependent on method of administration, diet, absence of similar strains (i.e., open niche space), and host genetics.12,232,233,234 Shifts in the gut microbiome and host environment following fermented food consumption likely play an additional role in engraftment success, offering additional complexity and opportunity for targeted incorporation of missing key members. Reports of enteric pathogens and antimicrobial resistance genes within commercial fermented foods highlight the importance of vigilance in monitoring the microbes that inhabit fermented foods.235

While current evidence shows an exciting role for fermented foods in modulation of the gut microbiome community, future clinical work would shine a light on a number of open questions: (1) understanding the role of specific fermented foods, including duration and conditions of fermentation and storage, in modulating the gut microbiome; (2) clinical trials across a number of cohorts, including those with clinical needs, to understand the limitations in the impact on the gut microbiome community; and (3) defining how differences in microbial load or pasteurization (or other post-fermentation processing) or cooking status might impact the gut microbial community.

Future directions and conclusions

While fermented foods offer potential for modulation of human health and disease through microbes and metabolites, expanded scientific understanding is needed at multiple levels. Foundational insight into the basic biology of fermented foods, such as the strains, genomes, metabolites, ecological succession, and stability of microbes over time is critical information to enable pursuing connections to human health. In addition, use of tools for secondary metabolite predictions, such as antiSMASH236 and MicrobeMASST,237 and application of both targeted and untargeted metabolomics will contribute greatly to the identification of metabolites at the interface of microbe-microbe and metabolite-host interaction. Such data will aid mechanistic studies that can employ model systems such as cell culture and animal models. The field of gut microbiome science serves as a useful template for advancing such investigation, and many of the experimental approaches are directly applicable. At the same time, human studies are needed to delineate which fermented foods at what levels of intake impact what biology in which cohort or population. These studies should include well-designed and carefully executed dietary interventions in healthy populations to survey changes in biology and physiology such as immune and metabolic parameters.

Additionally, clinical trials in patient cohorts targeting specific outcomes are necessary to support the incorporation of fermented food, or its components, into current medical practice; integral to medical use is the need for advanced types of quality control for the fermented food product to ensure safety and that specific bioactive components are present at required levels and no off-target effects are introduced. Whether there is a future for the prescription of medical fermented foods with certified microbial or metabolite abundances, particularly for groups with health vulnerabilities, remains an open area of exploration but will require a number of basic mechanistic questions to be addressed.

With unhealthy food driving many common diseases in the industrialized world, incorporation of fermented foods will also serve to replace commonly consumed foods that are incompatible with long-term health (e.g., ultra-processed, high glycemic). Fermented foods may serve as a gateway for consumers and patients to more broadly understand the power of diet to directly impact health. Several key points (Table 1) make fermented foods a candidate in catalyzing a movement toward expanded food-based health care. The ability of individuals to easily implement fermentation in their own kitchen enables economical production, engagement with food, and ability to customize to personal preferences; importantly, variation between at-home and commercial production of fermented foods remains to be explored, including heterogeneity in microbe and metabolite production between commercially available fermented foods. The wide variety of fermented foods also presents a wide range to meet the needs of people with different dietary restrictions and taste preferences. Indeed, the molecules produced during fermentation that dictate texture and flavor are likely to also play biological roles in many cases.

AreaStatus of fermentation researchEstablishedFuture area of research

General benefits of fermentation	• Enhanced food safety through organic acid and antimicrobial production; decreased abundance of potential pathogens23,29,67,70,71,72,73 • Increased nutrient availability (e.g., antioxidants and vitamins)53,54,55,56,57,58,59,60,61,62,63,64 • Substrate detoxification (e.g., cassava)78,79,80,82	• Fermented food microbiota strain-specific roles in nutrient enhancement, bioavailability, detoxification, flavor, and other final fermented food properties • Host factors affecting fermented food-derived nutrient absorption • Factors affecting microbial community development in starter and wild fermentation • Characterization of toxin production on novel substrates, including development of at-home food fermentation testing tools • Identification of commercially or medically useful fermented food products, e.g., antimicrobials to combat the rise of fungal pathogens and antibiotic resistance
Food fermentation microbiome-host interactions	• Consumption associated with trends toward decreases in markers of inflammation in healthy cohorts121,122,123,124,140	• Identification of metabolites produced during the food fermentation process across various substrates, including use of targeted and untargeted mass spectrometry, including LC- and GC-MS for broad compound discovery • Assessment of live microbe-host interaction compared to metabolite-host interaction, particularly in disease phenotypes • Characterization of metabolite-host interaction, including mechanism on host immune and enteroendocrine systems
Food fermentation microbiome-host microbe interactions	• Fermented food consumption increases gut microbiome diversity116,206,210	• Identification of source of microorganisms in spontaneously fermented foods • Role of fermented food consumption in engraftment • Role of fermented food microbe or metabolite in gut microbial community composition and metabolism
Beyond fermented food-gut interactions	• Effective models for the study of microbe-microbe interactions25,74,75,76	• Role of fermented food metabolites in gut-brain-axis signaling, particularly a role in satiety and hunger signaling • Application of fermentation for promotion of sustainability efforts238

Table 1

Areas to explore in fermented foods and health

• Open table in a new tab

Still, investigating the role of microbial metabolite production in a fermented food environment offers numerous intriguing yet understudied areas of research. Fermented foods lend themselves as simpler and tractable yet highly relevant models of microbe-microbe interactions compared to the human gut.76 Characterizing the fermented food metabolome and developing tools to better understand metabolite-microbe production dynamics within the fermented foods community has interesting applications for novel flavor and texture development. Transformation of unconventional substrates into familiar flavors can aid in sustainability efforts.238 In addition, with the growing interest in the gut-brain-axis research, the fermented food landscape offers a pool of understudied small molecules that might influence taste preference behavior,239,240,241,242 as well as novel compounds relevant to human health. Despite the exciting potential of fermented foods, research is still needed to understand the complexities.

AcknowledgmentsAuthor contributions

All authors developed the manuscript content and organization. E.B.C. wrote the manuscript and assembled figures. All authors read, edited, and commented on the manuscript.

Declaration of interests

The authors declare no competing interests.

References

1.

Marco, M.L. ∙ Sanders, M.E. ∙ Gänzle, M. ...

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on fermented foods

Nat. Rev. Gastroenterol. Hepatol. 2021; 18:196-208

Crossref

Scopus (300)

PubMed

Google Scholar

2.

Gänzle, M.

Fermented foods

Food Microbiology

ASM Press, 2019; 855-900

Crossref

Scopus (22)

Google Scholar

3.

Turnbaugh, P.J. ∙ Ley, R.E. ∙ Mahowald, M.A. ...

An obesity-associated gut microbiome with increased capacity for energy harvest

Nature. 2006; 444:1027-1031

Crossref

Scopus (9136)

PubMed

Google Scholar

4.

Sonnenburg, J.L. ∙ Bäckhed, F.

Diet–microbiota interactions as moderators of human metabolism

Nature. 2016; 535:56-64

Crossref

PubMed

Google Scholar

5.

Cabral, D.J. ∙ Penumutchu, S. ∙ Reinhart, E.M. ...

Microbial metabolism modulates antibiotic susceptibility within the murine gut microbiome

Cell Metab. 2019; 30:800-823.e7

Full Text

Full Text (PDF)

Scopus (63)

PubMed

Google Scholar

6.

Koppel, N. ∙ Maini Rekdal, V. ∙ Balskus, E.P.

Chemical transformation of xenobiotics by the human gut microbiota

Science. 2017; 356, eaag2770

Crossref

Scopus (565)

PubMed

Google Scholar

7.

Wu, W. ∙ Sun, M. ∙ Chen, F. ...

Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43

Mucosal Immunol. 2017; 10:946-956

Full Text

Full Text (PDF)

Scopus (303)

PubMed

Google Scholar

8.

Lavelle, A. ∙ Sokol, H.

Gut microbiota-derived metabolites as key actors in inflammatory bowel disease

Nat. Rev. Gastroenterol. Hepatol. 2020; 17:223-237

Crossref

Scopus (881)

PubMed

Google Scholar

9.

Caussy, C. ∙ Tripathi, A. ∙ Humphrey, G. ...

A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease

Nat. Commun. 2019; 10:1406

Crossref

Scopus (204)

PubMed

Google Scholar

10.

Kau, A.L. ∙ Ahern, P.P. ∙ Griffin, N.W. ...

Human nutrition, the gut microbiome and the immune system

Nature. 2011; 474:327-336

Crossref

Scopus (2003)

PubMed

Google Scholar

11.

Larraufie, P. ∙ Martin-Gallausiaux, C. ∙ Lapaque, N. ...

SCFAs strongly stimulate PYY production in human enteroendocrine cells

Sci. Rep. 2018; 8:74

Crossref

Scopus (231)

PubMed

Google Scholar

12.

Shepherd, E.S. ∙ DeLoache, W.C. ∙ Pruss, K.M. ...

An exclusive metabolic niche enables strain engraftment in the gut microbiota

Nature. 2018; 557:434-438

Crossref

Scopus (219)

PubMed

Google Scholar

13.

Zeng, X. ∙ Xing, X. ∙ Gupta, M. ...

Gut bacterial nutrient preferences quantified in vivo

Cell. 2022; 185:3441-3456.e19

Full Text

Full Text (PDF)

PubMed

Google Scholar

14.

David, L.A. ∙ Maurice, C.F. ∙ Carmody, R.N. ...

Diet rapidly and reproducibly alters the human gut microbiome

Nature. 2014; 505:559-563

Crossref

Scopus (6605)

PubMed

Google Scholar

15.

Fischer, C.N. ∙ Trautman, E.P. ∙ Crawford, J.M. ...

Metabolite exchange between microbiome members produces compounds that influence Drosophila behavior

eLife. 2017; 6, e18855

Crossref

Scopus (111)

Google Scholar

16.

Gribble, F.M. ∙ Reimann, F.

Enteroendocrine cells: chemosensors in the intestinal epithelium

Annu. Rev. Physiol. 2016; 78:277-299

Crossref

Scopus (401)

PubMed

Google Scholar

17.

Spivak, I. ∙ Fluhr, L. ∙ Elinav, E.

Local and systemic effects of microbiome-derived metabolites

EMBO Rep. 2022; 23, e55664

Crossref

Scopus (7)

PubMed

Google Scholar

18.

Vinderola, G. ∙ Sanders, M.E. ∙ Cunningham, M. ...

Frequently asked questions about the ISAPP postbiotic definition

Front. Microbiol. 2023; 14, 1324565

Google Scholar

19.

Guthrie, L. ∙ Spencer, S.P. ∙ Perelman, D. ...

Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes

Cell Host Microbe. 2022; 30:863-874.e4

Full Text

Full Text (PDF)

PubMed

Google Scholar

20.

Dunn, R.R. ∙ Wilson, J. ∙ Nichols, L.M. ...

ReviewVolume 36, Issue 4p684-701April 02, 2024Open Archive

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Our extended microbiome: The human-relevant metabolites and biology of fermented foods

Elisa B. Caffrey1 Send email to ecaffrey@stanford.edu ∙ Justin L. Sonnenburg1,2,3 Send email to justins2@stanford.edu ∙ Suzanne Devkota4,5 Send email to suzanne.devkota@cshs.org

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DOI: 10.1016/j.cmet.2024.03.007 External LinkAlso available on ScienceDirect External Link

Copyright: © 2024 Elsevier Inc. All rights reserved.

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Summary

One of the key modes of microbial metabolism occurring in the gut microbiome is fermentation. This energy-yielding process transforms common macromolecules like polysaccharides and amino acids into a wide variety of chemicals, many of which are relevant to microbe-microbe and microbe-host interactions. Analogous transformations occur during the production of fermented foods, resulting in an abundance of bioactive metabolites. In foods, the products of fermentation can influence food safety and preservation, nutrient availability, and palatability and, once consumed, may impact immune and metabolic status, disease expression‎, and severity. Human signaling pathways perceive and respond to many of the currently known fermented food metabolites, though expansive chemical novelty remains to be defined. Here we discuss several aspects of fermented food-associated microbes and metabolites, including a condensed history, current understanding of their interactions with hosts and host-resident microbes, connections with commercial probiotics, and opportunities for future research on human health and disease and food sustainability.

Keywords

1. fermentation
2. fermented foods
3. metabolomics
4. gut microbiome
5. microbial metabolites

Introduction

In food, fermentation includes “foods made through desired microbial growth and enzymatic conversions of food components,”1 occurring in aerobic and anaerobic contexts. The food fermentation process (see “What are fermented foods?” section) depends upon the microbial community to metabolize nutrients,2 altering the substrate (i.e., food) and producing metabolites and other molecules that can impact taste, texture, safety, and nutritional composition, as well as signal to the host and gut microbiome.

While this type of food fermentation happens ex vivo, a comparable microbial metabolism occurs in the gastrointestinal (GI) tract. Research on the gut microbiome has highlighted the importance of microbiome-derived metabolites in mediating human health and disease.3,4,5,6,7,8,9 By applying the same framework developed to study metabolite-host interactions in the gut, we can better understand the effects of fermented food metabolism on human health, offering an unexplored additional source of human-relevant microbial metabolites. From the perspective of the gut microbiome, fermentation can be defined as a primary metabolic process occurring in the absence of oxygen, such as the microbial consumption of complex carbohydrates in the colon. Dietary compounds metabolized by the gut microbiome lead to production of energy and metabolites, small chemical compounds that can influence the structure of gut microbial communities and signal directly to the host via interaction with different cell types within the gut10,11 or signal peripherally following absorption into circulation. Nutrients exiting the stomach that are not absorbed by the host small intestine make their way to the distal small intestine and colon, providing a pool of dietary compounds that gut microbes can access and metabolize.

Microbial strains that are well-matched to incoming nutrients tend to outcompete other members of the community, resulting in changes in the overall composition of the microbial community.12,13 This can occur within days of a major dietary change.14 The metabolites produced during microbial fermentation in the gut are a direct product of microbes that are being fueled by nutrient inputs. These compounds provide an energy source for other microbes; impact the ecosystem chemistry (e.g., pH); directly signal to the host, further restructuring the microbial community; and/or enter host systemic circulation, broadening metabolite reach.10,15,16,17 Postbiotics refer to the molecules that microbes produce18 as opposed to substrates that promote the growth of gut microbes, known as prebiotics. In this framework, diet can be considered a source of nutrients for both host and microbes, as well as a source of precursors for metabolites produced during fermentation by the gut microbiome.

There is a growing appreciation that microbially produced metabolites have a mediating role in health and disease, as seen in type 2 diabetes (T2DM), inflammatory bowel diseases (IBDs), and metabolic-associated fatty liver disease.3,4,5,6,7,8,9 Evidence of the influence of microbial-derived metabolites primarily comes from mechanistic studies, where they may promote health and disease states, as well as in their use as diagnostics or biomarkers. Production of these metabolites is influenced by a vast array of factors including diet, medications, baseline gut microbiota composition, and genetics.19 Similarly, metabolites produced during food fermentation offer a novel pool of signaling compounds that can interact with the GI tract, acting directly and indirectly on the host, with the potential to be further metabolized.

Consumption of fermented foods expands the possible interactions in the gut through increased chemical diversity. By considering food fermentation as an “extended microbiome,”20 a term previously used to describe fermented foods by Dunn et al.,20 we can reframe our relationship to fermented foods and their role in human health. Important considerations include how the practice of fermentation has shaped human biology, how fermented food consumption impacts health directly and indirectly, and future applications of food fermentation in biomedicine and extending beyond health. This review focuses on the role of metabolites as key mediators in the diet-microbe-host landscape, presenting current and potential roles fermented food microbiota-derived metabolites play in human health. We also review the need for expanded foundational information, such as characterizing the microbial communities and molecules associated with the wide array of fermented foods consumed globally.

What are fermented foods?

With the fermented food market expected to grow by over half a billion dollars in the next 4 years,21 fermentation has been of increasing research interest. Numerous reviews have offered an extended explanation of fermented food production.1,2 Here, we offer a brief summary.

Fermented foods (also referred to as ferments or microbial foods) are foods transformed by microbial growth and enzymatic conversions.1 During fermentation, members of the microbial community, which can include bacteria, yeast, or filamentous fungi, compete for resources with strain-specific nutritional and growth-condition preferences, accompanied by secretion of metabolites such as organic acids and antimicrobial peptides22,23 to gain advantage over competitors. Most fermented food is produced for specific sensory qualities including taste and aroma, which result from the production of specific metabolites. Key to the fermentation process is encouraging the growth of microbes through the manipulation of extrinsic factors such as temperature, pH, salinity, and humidity.

Where are the microbes coming from?

The source of microbes in a fermented food can be spontaneous, from a starter culture, or through “back-slopping.” In spontaneous fermentation, microbes from the environment (e.g., the surface of the raw ingredient, the hands of the producer, the room, and the equipment used to make the fermented food) initiate fermentation.24 While the initial microbial community will be more diverse, the raw ingredient and environmental factors will select for specific members of the community to dominate.25 Use of a starter culture (e.g., selected strain or group of strains) in a pasteurized substrate allows for a reliable final profile of the fermented food, preventing competition between the native microbial community and the added starter community. Starter cultures are widely used in fermented dairy production like yogurt and cheeses.20 In addition, starters can be constructed of characterized and sequenced strains deliberately chosen based on the presence or absence of specific traits, for example, to minimize the presence of antibiotic resistance genes that might be transferable to resident gut microbes.26 When a portion of a previous fermented food is incorporated into a next batch, propagating the microbial community, the process is called back-slopping fermentation2 and is analogous to subculturing or serial passage of microbial cultures in the lab. Examples of back-slopping include sourdough bread and kombucha,2,27 where a higher abundance of a previously successful microbial community can be used to initiate fermentation, although the community itself might be poorly characterized.

Dominant microbes involved in fermentation have been largely characterized, but there remains a need for the continued characterization of microbes involved in fermentation: in particular, characterization of microbes at lower abundance, which might play a role in shaping the microbial community or contribute to the metabolite pool. In addition, while there is general consistency in microbes that will be most abundant at the final stages of fermentation, like Lactiplantibacillus plantarum in vegetable fermentation or S. thermophilus and L. bulgaricus in yogurt, their final relative abundance, as well as the presence and abundance of other microbes in the community, remain variable from batch to batch. In line with microbial heterogeneity between fermentation batches, metabolite production and abundance will also be variable.28 Ongoing work modeling microbiota and metabolite dynamics during fermented food community assembly will shed light on how extrinsic factors might be used to decrease product variability.24

What does it mean for a food to be fermented?

While there are broad categories of microbes that can be involved in the fermentation process (e.g., lactic acid bacteria, acetic acid bacteria, filamentous molds, and yeast), lactic acid fermenting microbes are one of the most common classes, seen in the fermentation of many vegetables, dairy, and grains (e.g., kimchi, yogurt, and injera). In lactic acid fermentation of vegetables, addition of salt and access to preferred carbohydrate nutrient sources promote growth of halophilic lactic acid bacteria (LAB), leading to early community dominance and secretion of antimicrobial peptides and organic acids (predominantly lactic acid), further enhancing growth.29,30,31 LAB outcompetes potential spoilage-associated microbes and competitors, excluding undesirable microbes from the final ferment. Secretion of protein hydrolases to enhance nutrient accessibility, shown primarily in mold fermentation microbes like Aspergillus oryzae and Rhizopus oryzae, not only promotes fungal growth but also plays an important role in enhanced palatability of the fermented food. Additional metabolites produced during this process play important roles in enhancing palatability and food safety and mediate microbe-microbe and microbe-host interactions. It is important to note that many non-fermented foods are produced to mimic the flavor and preservation of fermented foods (e.g., vinegar/salt brined pickles).1 Manufacturers may add viable microbes to pickled foods or pasteurized fermented foods at the end of production, attempting to recreate the living microbial content of raw fermented foods and enabling “probiotic” or “contains live microbes” label claims; in many cases the supplemented microbes are different strains than those associated with fermentation and may be spores and therefore not metabolically active. Microbial density of lactic acid ferments ranges widely across products and can reach 105–1010 CFU/g32 with the microbes producing and consuming metabolites during microbial growth. While addition of probiotic microbes to consumer-ready food products increases CFU count, fermentation (and the accompanying metabolite production) does not occur. Therefore, the simple presence of bacteria or fungi on an ingredient label does not necessarily mean it is a fermented product. For example, an olive brined in dilute lactic acid and salt with spores of a Bacillus species (distant relative of Lactobacillus that is able to form spores) added before sealing can create a shelf-stable product with highly reproducible flavor that mimics a lactic acid ferment and enables a claim of “contains live microbes.” However, such a product deviates significantly from a traditionally fermented olive. Data are lacking as to whether mimicking food fermentation by adding purified metabolites or live microbes has the same benefit, particularly when consuming microbes distinct from those that are typically found in fermented foods. Also, in the addition of probiotics (considered "dietary supplements") to food FDA draft guidelines recommend including the total weight of the added microbial mass and CFU of viable microbes, with no recommendation as to maximum allowed supplemented probiotic CFU or weight count.33 While estimates from the National Health and Nutrition Examination Survey (NHANES) data show there is a trending increase in consumption of foods containing live microbes in the American diet, estimates of CFUs or microbial type are still lacking.34 Characterizing the typical range of dietary microbe consumption and defining a healthy personalized range is necessary for the establishment of dietary recommendations and regulation of commercial products.35

Fermented foods: A brief history

While the earliest evidence of human engagement with food fermentation dates back to at least 14,000 years BCE,36 evolutionary genetics support a much longer relationship between humans and food-derived microbially produced metabolites. Roughly 10 million years ago, corresponding to the movement of our great ape ancestors from trees to the forest floor, evolution of the alcohol dehydrogenase class IV (ADH4) enzyme allowed our hominid ancestors to metabolize ethanol, likely a primary metabolite produced by yeast spontaneously fermenting fallen fruit.37 Over the course of human history, food fermentation has been practiced by most culinary traditions, dependent on substrate availability.20 The use of fermented ingredients is not uncommon in historical medicinal practices, with documented use of wine, doenjang (Korean fermented soybean paste), and garum (fermented fish sauce)38,39,40 for the treatment and prevention of ailments. The modern conceptualization of microbial foods as “health foods” stems from Élie Metchnikoff, who hypothesized Bacillus bulgarian (now Lactobacillus delbrueckii subsp. bulgaricus), which had been isolated from Bulgarian curdled milk referred to as “yahourth,” was responsible for the increased longevity observed in the Balkan population compared to other European populations. Work on the isolation and administration of this strain established probiotics as both a concept and a commercial product (Box 1). A revitalization of at-home fermentation production41 accompanied by the rise in the commercial fermented food market21 has focused on marketing fermented foods for “health” properties, although there is a lack of consensus on how and in what context health can be defined.35 Here we present the current understanding and limitation of the use of microbial foods for human health, focusing on the role of metabolites as microbe-host mediators and highlighting areas of future research.

Box 1

Fermented foods and probiotics

L. delbrueckii subsp. bulgaricus is one of the key starter strains used to make yogurt today42 and was also the first described probiotic,43 isolated from fermented dairy. The term probiotic refers to a well-defined and characterized live microorganism with demonstrated health benefits,1 which might be consumed in pure form (e.g., probiotic pill) or added to a food (e.g., probiotic yogurt). According to this definition, fermented foods made with spontaneous fermentation or through back-slopping do not fit the formal definition of probiotic unless the microbiome of the fermented food has been characterized and the strains are proven to exert health benefits. In commercial fermented food preparation, probiotic strains might be added into the yogurt once fermentation is complete, as with L. plantarum and L. rhamnosus,44 two strains also found in fermented foods,45 or many of the Bifidobacterium spp. strains that are not associated with food fermentation but rather were isolated from other sources such as infant feces.46,47

While probiotics have been extensively reviewed,48 success in trials is highly variable and appears dependent on a number of factors. A randomized, double-blind, placebo-controlled study looking at the impact of stomach acid on probiotic intervention showed that suppression of stomach acid production with proton pump inhibitors (PPIs) might enhance probiotic effectiveness, possibly via improved viability.49 More recently, a randomized controlled trial looking at the effects of probiotics on metabolic syndrome identified diet as a key differentiating factor between responders and non-responders, with non-responders having higher levels of serum glucose and insulin at the end of the intervention.50 Unexpectedly, total and added sugar, lactose, and sucrose intake was higher in the probiotic responders compared to non-responders. Further research is needed to better understand basic interactions between probiotics, diet, host gut microbiome, and host.

Current research points to metabolites and other probiotic products (sometimes commercially referred to as “postbiotics”) as key contributors to many of the benefits seen by probiotic consumption.18,51 While probiotics offer a characterized bacteria for a specific indication, in supplement form these products lack fermentation end products. Alternatively, fermented foods offer an extensive reservoir of potential postbiotics that can directly impact the microbiome, immunity, and enteroendocrine system.

The extended microbiome

Metabolites produced during fermentation provide a key role in the increased safety,52 nutrient availability,53,54,55,56,57,58,59,60,61,62,63,64 and enhanced gustatory qualities22,65,66 of fermented foods. Understanding how the microbial strains present combined with other factors, including salinity, pH, and temperature, contribute and influence metabolite production remains a necessary consideration when characterizing the final fermented product, particularly when it comes to food safety.

Enhancing food safety

Preserving food through fermentation is a reliable technique to enhance safety and stability over a prolonged period of time. During fermentation, metabolites produced during microbial competition for nutrients inhibit growth of competitors, concomitantly preventing growth of potential human pathogens. Production of various organic acids, primarily lactic or acetic acid, decrease the pH and create an inhospitable environment for food-borne pathogens like C. botulinum, L. monocytogenes, E. coli O157:H7, and S. flexneri.67,68,69 Secretion of antimicrobial compounds like bacteriocins, antibacterial peptides with both narrow and broad-spectrum activity, has been extensively studied in fermented food-associated LAB, including in kimchi, cheese, and fermented cereals,23,29,70,71 and shows high specific activity against known food pathogens.29 To date in the US, no cases of botulism have been reported in vegetable fermentation, mold-based fermentation, or dairy fermentation,72 with the rare cases being home-fermented meats, including beaver tail and uneviscerated fish, and tofu.73

Much of the insight into the mechanisms underlying the ecology of fermented foods has come from their use as a model microbial ecosystem. One example is the identification of novel antimicrobials that mediated microbe-microbe interactions,25,74,75 highlighting fermented foods as a potentially rich source of novel antimicrobials for medical application. More generally, the reduced microbial diversity in fermented foods compared to the gut microbiome provides improved tractability for exploring community assembly, transkingdom interactions, strain-diversity, and microbial evolution.76

Fermentation can also enhance food detoxification. Raw cassava, a starchy tuberous root native to South America and a staple food for over 500 million people,77 contains high levels of neurotoxic cyanogenic glycosides,78 which can be reduced by >70% through fermentation,79 with L. plantarum and Loigolactobacillus coryniformis believed to play a major role.80,81 Consumption of unprocessed cassava can lead to development of the irreversible neurological disorder konzo, which disproportionately affects rural areas in Africa.82 Gaining mechanistic insight into cassava detoxification would allow for improvement in food safety, with potential application to other foods.

Increasing nutrient availability and antioxidants

Fermented foods also have a documented history of use as nutrient supplements. James Cook, the British explorer, successfully prevented and treated scurvy among his crew by instructing them to consume 2 lb. of sauerkraut each a week, estimated to provide about 150 mg of ascorbic acid.53 However, these increased concentrations in nutrients might be specific to the microbial strains found in the ferment. Early work looking at prevention of scurvy in guinea pigs fed commercial sauerkraut found that two of the sauerkrauts successfully prevented scurvy while two other sauerkrauts did not. No difference was identified between the sauerkraut manufacturing conditions; however, microbial communities that might be involved in the observed differences were not investigated for potential differences.54 More recent studies support an increase in vitamins and nutrients in fermented foods compared to unfermented ingredients, including vitamins C, B2, B12, and K and folate.55,56,57,58,59,60,83 Additionally, release of encrypted bioactive components like polyphenol and flavonoid from tea leaves over the course of kombucha production increases antioxidant content of the drink.61 There is some rodent evidence pointing to host benefits following consumption of fermentation-driven enhanced nutrient bioavailability62,63; however, the chemical complexity combined with depletion of precursors (e.g., glucose) provides many confounders. Additional work is needed to isolate the effects of the wide array of relevant variables such as (1) diversity and variability in nutrients across fermented food; (2) the fermented food microbiota at a strain-specific level; and (3) elucidating factors, including host and microbiome genetics, that can impact nutrient absorption.

Flavor and taste

Fermentation is often practiced for its culinary use, where transformation of taste, smell, texture, and other sensory stimuli of the food during this metabolic process acts in synthesis to change the perceived flavor of the food. Spoilage is often associated with “off-flavors,” while novel flavors not typically associated with the starting ingredient are often a desired result of the fermentation process. For example, carbohydrate fermentation can result in the production of thiazoles and furfural, associated with nutty and almond-like flavors84,85 via sugar degradation and Maillard reaction pathways. Promotion of the Ehrlich pathway, an amino acid catabolic process, during fermentation can also lead to an increase in sulfur-containing, aromatic, and branched-chain volatiles like 2-phenylethanol, associated with a rose-like odor.30,86 Other metabolites like organic acids, flavonoids, and polyphenols can also contribute to the change in flavor of the final ferment.22,65 In addition, filamentous fungi can secrete hydrolases during fermentation,87 increasing simple amino acids and oligosaccharides and thus promoting umami and sweet taste sensation.

As expression‎ of sweet, bitter, and umami sensors is not limited to the oral cavity but expressed across the human GI tract,88 metabolites typically associated with flavor may play a role beyond the host gustatory system, particularly when coupled with nutrient absorption. Sensing of sweetness by T1R2/T1R3, a G protein-coupled receptor (GPCR) heterodimer expressed in enteroendocrine cells (EECs) in the human gut, can promote secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2).89,90,91 Activation of T1R2/T1R3 is not limited to sucrose but includes a variety of sweet-tasting stimuli including fructose and lactose, sweet amino acids such as glycine and d-tryptophan, sweet proteins such as monellin and thaumatin, and synthetic sweeteners such as aspartame and sucralose. Whether these ligands promote the same downstream T1R2/T1R3-mediated effects remains to be explored.92 Similarly, the GPCR T1R1/T1R3 mediates umami taste perception in the gut. The heterodimer is activated by L-amino acids such as monosodium glutamate (MSG; sodium L-glutamate) or L-cysteine and potentiated by inosine 5′-monophosphate (IMP) and other nucleotides. Activation of T1R1/T1R3 by MSG initiates peristaltic reflexes in rodent models, along with secretion of the pain-mediating neurotransmitter CGRP (calcitonin gene-related peptide) in the colon.93 CGRP receptor antagonists and anti-CGRP ligand monoclonal antibodies have more recently been approved for treatment and prevention of migraines.94

In humans, bitter taste perception is mediated by 25 putative members of the TAS2R (taste 2 receptor) GPCR family. Use of the bitterant caffeine has been shown to promote gastric acid secretion in the stomach through the TAS2R43 receptor,95 as well as lead to gut-derived serotonin secretion. Matured hop bitter acids (MHBAs), often added in the production of beer, have been shown to increase production of cholecystokinin (CCK) production by EECs,96 which plays a role in anorexigenic signaling and gastric emptying.97 Interestingly, olfactory receptors (ORs), a class of GPCRs typically found in the olfactory mucosa, have also been identified in the human gut. In purified form, the aromatic compound citronellal, also a volatile product of yeast geraniol fermentation in beer and wine production98,99,100 with an intense lemon scent, has been shown to stimulate GLP-1 secretion in both a human EEC line and mouse tissue across the small intestine.101 These examples illustrate the ability of molecules that trigger taste perception to impact host physiology. With growing interest in fermentation as a source of novel flavors,66 flavor-associated metabolites could impact important biological processes such as secretion of gut-derived peptides. Greater mechanistic insight into the roles metabolites produced during fermentation play both in perception of flavor and host biology is an exciting area for exploration, particularly focusing on how flavor-associated metabolites can modulate EECs (discussed later). In addition, inclusion of taste-preference and taste-perception surveys when conducting clinical fermented food research would aid in translatability and facilitate broader research into taste-associated compounds in food fermentation.

Food fermentation: Metabolite-host interactions

Consumption of a fermented food includes potential benefits beyond increased nutrient availability and food safety.58,64,45 In the gut, microbiome-derived metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids signal to the host through a variety of receptors, including transcription factors and GPCRs, playing a role in host incretin secretion, energy expenditure, and immune response.102,103,104,105,106 Insight into metabolite production in fermented foods will allow us to map similar metabolite-GPCR interactions, allowing deeper understanding of the role fermented food-associated microbes play in the host.

Metabolites and intestinal receptors

Gut microbiota-derived nicotinic acid,107 butyrate, and β-hydroxybutyrate produced in a ketoacidosis state108 can activate the hydroxycarboxylic acid receptor 2 (HCA2), expressed in a number of cell types, including the gut epithelium.109 Activation has been shown to have downstream anti-inflammatory effects,110,111 while chronic inflammation has been shown to downregulate HCA2 expression‎.112,113 HCA2 activation has also been shown to play a role in increasing bone density in weanling mice114 and suppresses NF-κB activation in colonic cell lines and in mouse colonic tissue.109 Additional metabolites, including hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3−PPA), activate HCA2.107 HA and 3-3−PPA are both products of hydroxycinnamate reduction in L. plantarum,115 commonly found in vegetable fermentation. While GPCRs are expressed across multiple cell and tissue types, their expression‎ on immune and EECs makes them of particular interest in understanding metabolite-host interaction in metabolic and immune disorders.

One of the indications of this fermented food metabolite-host relationship is the hydroxycarboxylic acid receptor 3 (HCA3). Described by Peters et al.,116 while most mammals express HCA1 and HCA2, only great apes (including humans) and siamang have an active HCA3, with humans exhibiting strongest activation. D-phenyllactic acid (D-PLA) is the only known HCA3 ligand117,118 and is produced by LAB. Measured in high concentrations in sauerkraut and up to 12.0–21.1 μg/mL in kimchi,119 it is elevated in the plasma following sauerkraut consumption.116 Lack of adequate animal models and currently no known HCA3 inhibitor has remained a challenge to the understanding of the biological relevance of HCA3.120 However, HCA3 expression‎ in human innate immune cells and adipose tissue lends to the hypothesis that HCA3 activation plays a role in host immuno-metabolism and energy storage.116 The extent to which consumption of other lactic acid-based ferments (including yogurt) can activate this receptor remains to be explored.28 Examining the effects of two primary fermented food metabolites, lactic and acetic acid, provides insight into how food fermentation can impact the host immune system. When produced by the host or gut microbiota, lactic acid activation of macrophage GPR81 reduces inflammatory responses in the colon.121,122 Oral administration of lactic acid increases microbiota-dependent regulatory T cells in the small intestine, promoting immune tolerance.123 Gut microbiota-derived acetate increases colonic IgA production and alters the capacity of the IgA pool to bind to specific members of the microbial community.124 Effects of dietary acetate have been primarily studied in disease models (Figure 1). The role of dietary acetate in healthy models remains an open area of investigation, with open questions similar to lactic acid. For both lactic and acetic acid, there is a need to (1) define the variability in organic acid production by microbial community and fermentation time point, (2) characterize the bioavailability of organic acids based on substrate type (sauerkraut compared to yogurt), and (3) gain further mechanistic insight into the downstream impact of organic acid consumption based on dosage and location of the metabolite-receptor interaction.

Figure 1 Fermented food microbes and metabolites can influence the immune system, endocrine system, and host gut microbiome

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Additional metabolites previously identified in fermented foods, including the host immune-modulating metabolite D-PLA, have been shown to reach μM plasma concentrations following ingestion of sauerkraut.116 A randomized human dietary intervention showed consumption of fermented foods leads to decreased markers of inflammation140 while promoting increased gut microbiome diversity when compared to a high-fiber-consuming cohort. In this study, specific serum metabolites, which may be derived from diet, microbiome, or host (or combinations thereof), correlated with specific aspects of the immune response. Expanded understanding of fermented food metabolites, their absorption, and interaction with human biology is the next step in characterizing ferment-immune interplay (Figure 2).

Figure 2 Metabolic paradigms of fermented food-derived metabolites

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EECs are hormone-producing cells accounting for about 1% of the gut epithelium. Acting at the interface between luminal content and host signaling, EECs produce more than 20 hormones in response to nutrient absorption. These hormones can signal systemically to the pancreas as well as the brain via vagal afferent neurons.175 While EECs can be stimulated directly by nutrients consumed, colonic EECs are also activated by bacterial SCFAs, notably butyrate and propionate, resulting from fiber fermentation. EEC-type distribution changes across the GI tract, with hormones like ghrelin and GIP primarily found in the upper small intestine and GLP-1 and peptide YY (PYY) primarily found in the colon,16 resulting in region-specific effects.129,176,177,178 Specific changes in gut colonization status, such as the absence of a microbiota (germ-free mice) or administration of a probiotic (Limosilactobacillus reuteri), have shown to increase GLP-1 levels, highlighting a role for microbial signaling in incretin regulations (reviewed in Arora et al.178). Recently, Akkermansia muciniphila has been shown to secrete a GLP-1-inducing metabolite, resulting in a reduction of a high-fat-diet-induced metabolic defects in mice.179 In conventional mice, PYY-positive EEC numbers increase in the colon in the presence of SCFAs via an FFA2-dependent pathway, reflected by an increase in circulating PYY, an enteroendocrine anorectic hormone.180 In humans, a study in individuals with diabetes consuming fermentable fibers for 84 days, with hemoglobin A1c (HbA1c) as primary endpoint, showed that those in the fiber arm resulted in significant reduction of HbA1c and fasting blood glucose at the end of the study. The authors found this was due to an increase in butyrate-producing bacteria and measured increases in butyrate levels resulting in significantly increased blood levels of GLP-1 and PYY over time.181 Another human study found that direct delivery of the SCFA propionate bound to inulin successfully delivered the propionate to the colon, resulting in significantly increased PYY and GLP-1 240 min after consumption of the oral propionate. Six months of daily supplementation resulted in attenuated weight gain and reduced intrahepatic lipids.182 Just as metabolites produced by the gut microbiota can influence host biology, metabolites produced during food fermentation can have similar interactions. The diversity of metabolites, many of which are likely to be distinct from those produced by gut-resident microbes, and interactions with microbes and host receptors in the small intestine likely produce an array of biological effects remain to be defined.

Ghrelin-secreting EECs also express GPR81, where lactate binding inhibits secretion of this “hunger hormone.”146 Unlike GLP-1-producing cells, which are primarily located in the colon, ghrelin-producing cells are primarily located in the stomach and duodenum, where they are more likely to interact with fermented food-derived lactic acid, with downstream effects on hunger signaling and metabolism. Additionally, mapping fermented food metabolites to GPCR receptors, particularly the number of orphan GPCRs,183 would allow for potential identification of novel GPCR-ligand pairings, expanding the development of a mechanistic framework of microbe-host interactions2 and allowing for a targeted exploration of downstream effects.

Fermented foods in human disease

The rise in health claims about fermented foods is not matched by an increase in clinical evidence. The few current studies are primarily focused on assessing the impact of fermented food on healthy individuals,23,140 with few studies looking at the role of fermented foods in patients with health conditions. Early data from irritable bowel syndrome (IBS)184,185 and metabolic diseases186,187,188,189 (including T2DM and obesity) offer examples of how fermented foods can improve human health through altering nutrient accessibility and impacting the human microbiome. These positive outcomes highlight the need for a greater understanding of the fermented food metabolome landscape to pursue molecular mechanistic mediators.

Meta-analyses of observational studies support a role of fermented dairy intake for the decreased risk of T2DM and cardiovascular disease.186,187,188,189 However, human clinical trials looking at the risk and prevention of these diseases in the context of fermented food consumption are lacking, with the strongest current evidence coming from animal models.190 A recent study on yogurt consumption in obese mouse models identified branched-chain hydroxy acids (BCHAs) produced during LAB-driven yogurt fermentation can supplement host BCHAs and improve metabolic parameters, including improved glucose tolerance and resistance to high-fat, high-sucrose diet-induced obesity. The effects appear to be driven by production of three hyodeoxycholic acids, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, and alpha-hydroxyisovalerate, produced by the gut microbiome.191

Kimchi consumption has also been studied for its impact on health, but few clinical trials have looked at the impact of consumption on metabolic disease. A small crossover clinical trial in obese patients reported significant decreases in body fat and improved metabolic markers.192 A follow-up crossover clinical trial followed prediabetic participants over the course of a 16-week period, reporting a decrease in insulin resistance and increased insulin sensitivity during the period of 10-day fermented kimchi consumption compared to 1-day fermented (defined as “fresh”) kimchi.193 Insight into how fermentation-derived metabolites impact secretion of incretin hormones like GLP-1 is an important step in understanding the mechanistic implications of fermented food consumption. Incorporating measurements of the foods’ differences in chemical composition, patient incretin hormones, insulin, and blood glucose in future clinical trials would greatly aid the understanding and translatability of laboratory work on fermented food metabolite-induced responses. There remains a clear need for randomized human clinical trials and mechanistic interrogation into how the fermented food microbiome and its metabolites interact with the host, including the resident microbial landscape.

While exploring fermented foods for health benefits remains an exciting frontier, there are examples where metabolites produced during fermentation can lead to negative health consequences in sensitive health populations. Biogenic amines are amino acid derivatives produced during fermentation that can include tyramine, histamine, cadaverine, and putrescine, with tyramine and histamine being of particular interest. Even small amounts of dietary tyramine (8–10 mg) can lead to hypertensive episodes in the presence of the antidepressant class monoamine oxidase inhibitors,194 with occasional fatalities reported.195 Dietary tyramine is increased in ferments like fish sauce, sauerkraut, and aged cheeses, but abundance can vary widely depending on food and fermentation time196; thus, patient dietary recommendations need to consider sensitivity, food type, serving size, and drug interactions. While tyramine production is enhanced by increased sodium content in the ferment, a variety of approaches have been applied to limit tyramine production during fermentation. For example, successful tyramine reduction was achieved with the addition of tyramine- or tyrosine-oxidizing LAB in a micro-cheese model.197 Similarly, certain LAB associated with food fermentation have been described as histamine producers, including Lentilactobacillus parabuchneri, Lentilactobacillus buchneri, and Oenococcus oeni,198,199,200,201 primarily with proteinaceous substrates like in dairy and meat ferments. While recommendations for a low-histamine diet show high efficacy for histamine hypersensitivity, fermented foods show a wide range of histamine abundance, with length of fermentation time, storage, and cooking method all influencing histamine abundance at ingestion.202 Mechanistic understanding of histamine production, characterization of extrinsic factors impacting production, and rapid biogenic amine detection methods are all necessary both from a clinical and a consumer perspective. It is likely that extending such detection methods to other biomolecules will aid in quality control and inform health claims, particularly as potential benefits of fermented foods on other physiological aspects are explored further.

Previous studies have shown associations of fermented food or pickled vegetable (terms used interchangeably in the studies; see “What are fermented foods section”) intake and esophageal and stomach cancer.203,204,205,206

These concerns are related to retrospective studies where the quality and contamination of the fermented foods was not tested, and many confounders exist. For example, one widely cited study published in 1980 focused on the preval‎ence of esophageal cancer in Northern Chinese populations,203 with data from 1959 to 1970. The study found a positive correlation between “pickled vegetable” consumption (likely fermented based on literature description) and esophageal cancer risk, but due to long fermentation storage period, the authors note that much of the food became covered with a white mold. This association was also seen in regions with higher consumption of laozao, a fermented sweet grain dish. However, samples were found to have high fungal contamination, including Aspergillus flavus, associated with increased production of carcinogenic compounds.207,208,209,210,211 In addition, enzymatic activity of other molds in the sample is hypothesized to allow for synthesis of N-nitroso compounds, associated with higher cancer risk.212,213 With the exception of dairy fermented products that are primarily produced using well-defined cultures, vegetable ferments and kombuchas are largely driven by spontaneous fermentation or uncharacterized microbial communities, respectively. However, fermented food found at grocery stores is required to meet hazard analysis critical control point (HACCP) compliance and go through rigorous safety testing before being commercially available, significantly decreasing the risk of contamination by toxin-producing microbes. Conversely, several studies have shown fermented food intake is associated with no increased risk or a decreased risk from certain cancers and diabetes.186,188,189,214,215,216,217,218 Future prospective studies with better characterization and documentation of types of fermented foods consumed are required to understand if such concerns are valid.

Food fermentation: Microbe-microbe interactions

Composition of an individual’s gut microbiome is influenced by host genetics and lifestyle, including diet, medical practices, and environment. Studies comparing gut microbial composition across different lifestyles note decreasing gut microbiome diversity in industrialized populations, believed to be driven by factors associated with an industrialized lifestyle including antibiotic overuse, high-fat and high-sugar diet, and decreases in breastfeeding.219 Not only does immigration to an industrialized environment from a non-industrialized environment lead to a decrease in microbial diversity,220 but this decrease in microbial diversity compounds over time and over the course of generations.219,220,221,222 Within industrialized populations, more diverse gut microbiomes are a conserved metric associated with resistance to Western-associated diseases, such as T2DM, heart disease, and colorectal cancer.223,224,225 Understanding how diet can increase an individual’s microbiome diversity is an active topic of research in the gut microbiome field. Fermented food consumption appears to be a promising tool in gut microbiome reconstruction.

Fermented foods and the human gut microbiome

Dietary nutrients and host-derived metabolites, including lactate and 3-hydroxybutyric acid, can impact the human gut microbiome, shifting microbial composition with downstream implications for host health from metabolic disease to immune status.13,19,177 Similarly, fermented food consumption appears to have important effects on the gut microbiome. The American Gut Project, a citizen science project, reported subtle but significant shifts in the beta-diversity and taxa of fermented food consumers compared to non-consumers across 6,811 participants. Of interest, fermented food consumers had an increase in conjugated linoleic acid (CLA) producers and fecal CLA,226 fatty acid metabolites that activate the nuclear receptor PPAR-γ227,228 to exert beneficial health effects on a number of conditions including IBD and T2DM.

A randomized clinical trial comparing high fermented food consumption to high fiber consumption showed fermented food consumption increased gut microbiome diversity compared to baseline, with alterations in the gut microbiome composition that were durable beyond the trial period.140 Nine amplicon sequence variants (ASVs) in the Firmicutes phylum increased across high fermented food compared to high fiber, including four members of the Lachnospiraceae family, two Ruminococcaceae, and one Streptococcaceae. This increase in gut microbiome diversity was not observed in the fiber-consuming groups. This trend in increased microbiome diversity has been further supported by a more recent randomized control trial comparing gut microbial composition following 6 weeks of fermented vegetables, pickled vegetables, or no vegetables.229 Not only was there an increase in gut microbiota diversity from baseline to completion of the study in the fermented vegetable group, but microbiota diversity did not change in the pickled vegetable or non-vegetable consumer group. Remaining questions include whether this increased diversity is mediated via host immune effects, live microbes in the fermented foods, metabolites alone, or other macromolecules and how durable the response is after cessation of fermented food consumption.

Interestingly, the majority of microbes responsible for the increase in diversity were not from the ferments and were likely either acquired from the environment or present in the hosts before the intervention but below detection limits. Whether fermented foods may act as a source of microbes to increase diversity or lead to compositional shifts that promote incorporation of transient microbes remains to be understood. Very few studies have assessed human microbiota composition before, during, and after fermented food consumption.140,229 A study comparing mother-infant strain sharing in a rural Ethiopian cohort identified two microbes from injera (Fructilactobacillus sanfranciscensis and Lactiplantibacillus xiangfangensis), a locally produced teff flour ferment, as contributors to diversity in maternal-infant cohorts.230 However, due to the popularity of injera consumption, whether these microbes were transient or had become incorporated into the gut microbiome could not be determined.

Comparison of LAB genomes from fermented foods to the human microbiome reveals distinct sequences, supporting the idea that fermented foods are a transient source of LAB for the gut microbiome. Differences in LAB species identified across Western and non-Western gut microbiome populations appear to reflect lifestyle.231 Understanding which LABs are transient or engrafted stable members of the gut community should be aided by more investigation and improved genomic resolution. Early work on engraftment into the gut microbial community shows successful incorporation of microbes is largely dependent on method of administration, diet, absence of similar strains (i.e., open niche space), and host genetics.12,232,233,234 Shifts in the gut microbiome and host environment following fermented food consumption likely play an additional role in engraftment success, offering additional complexity and opportunity for targeted incorporation of missing key members. Reports of enteric pathogens and antimicrobial resistance genes within commercial fermented foods highlight the importance of vigilance in monitoring the microbes that inhabit fermented foods.235

While current evidence shows an exciting role for fermented foods in modulation of the gut microbiome community, future clinical work would shine a light on a number of open questions: (1) understanding the role of specific fermented foods, including duration and conditions of fermentation and storage, in modulating the gut microbiome; (2) clinical trials across a number of cohorts, including those with clinical needs, to understand the limitations in the impact on the gut microbiome community; and (3) defining how differences in microbial load or pasteurization (or other post-fermentation processing) or cooking status might impact the gut microbial community.

Future directions and conclusions

While fermented foods offer potential for modulation of human health and disease through microbes and metabolites, expanded scientific understanding is needed at multiple levels. Foundational insight into the basic biology of fermented foods, such as the strains, genomes, metabolites, ecological succession, and stability of microbes over time is critical information to enable pursuing connections to human health. In addition, use of tools for secondary metabolite predictions, such as antiSMASH236 and MicrobeMASST,237 and application of both targeted and untargeted metabolomics will contribute greatly to the identification of metabolites at the interface of microbe-microbe and metabolite-host interaction. Such data will aid mechanistic studies that can employ model systems such as cell culture and animal models. The field of gut microbiome science serves as a useful template for advancing such investigation, and many of the experimental approaches are directly applicable. At the same time, human studies are needed to delineate which fermented foods at what levels of intake impact what biology in which cohort or population. These studies should include well-designed and carefully executed dietary interventions in healthy populations to survey changes in biology and physiology such as immune and metabolic parameters.

Additionally, clinical trials in patient cohorts targeting specific outcomes are necessary to support the incorporation of fermented food, or its components, into current medical practice; integral to medical use is the need for advanced types of quality control for the fermented food product to ensure safety and that specific bioactive components are present at required levels and no off-target effects are introduced. Whether there is a future for the prescription of medical fermented foods with certified microbial or metabolite abundances, particularly for groups with health vulnerabilities, remains an open area of exploration but will require a number of basic mechanistic questions to be addressed.

With unhealthy food driving many common diseases in the industrialized world, incorporation of fermented foods will also serve to replace commonly consumed foods that are incompatible with long-term health (e.g., ultra-processed, high glycemic). Fermented foods may serve as a gateway for consumers and patients to more broadly understand the power of diet to directly impact health. Several key points (Table 1) make fermented foods a candidate in catalyzing a movement toward expanded food-based health care. The ability of individuals to easily implement fermentation in their own kitchen enables economical production, engagement with food, and ability to customize to personal preferences; importantly, variation between at-home and commercial production of fermented foods remains to be explored, including heterogeneity in microbe and metabolite production between commercially available fermented foods. The wide variety of fermented foods also presents a wide range to meet the needs of people with different dietary restrictions and taste preferences. Indeed, the molecules produced during fermentation that dictate texture and flavor are likely to also play biological roles in many cases.

AreaStatus of fermentation researchEstablishedFuture area of research

General benefits of fermentation	• Enhanced food safety through organic acid and antimicrobial production; decreased abundance of potential pathogens23,29,67,70,71,72,73 • Increased nutrient availability (e.g., antioxidants and vitamins)53,54,55,56,57,58,59,60,61,62,63,64 • Substrate detoxification (e.g., cassava)78,79,80,82	• Fermented food microbiota strain-specific roles in nutrient enhancement, bioavailability, detoxification, flavor, and other final fermented food properties • Host factors affecting fermented food-derived nutrient absorption • Factors affecting microbial community development in starter and wild fermentation • Characterization of toxin production on novel substrates, including development of at-home food fermentation testing tools • Identification of commercially or medically useful fermented food products, e.g., antimicrobials to combat the rise of fungal pathogens and antibiotic resistance
Food fermentation microbiome-host interactions	• Consumption associated with trends toward decreases in markers of inflammation in healthy cohorts121,122,123,124,140	• Identification of metabolites produced during the food fermentation process across various substrates, including use of targeted and untargeted mass spectrometry, including LC- and GC-MS for broad compound discovery • Assessment of live microbe-host interaction compared to metabolite-host interaction, particularly in disease phenotypes • Characterization of metabolite-host interaction, including mechanism on host immune and enteroendocrine systems
Food fermentation microbiome-host microbe interactions	• Fermented food consumption increases gut microbiome diversity116,206,210	• Identification of source of microorganisms in spontaneously fermented foods • Role of fermented food consumption in engraftment • Role of fermented food microbe or metabolite in gut microbial community composition and metabolism
Beyond fermented food-gut interactions	• Effective models for the study of microbe-microbe interactions25,74,75,76	• Role of fermented food metabolites in gut-brain-axis signaling, particularly a role in satiety and hunger signaling • Application of fermentation for promotion of sustainability efforts238

Table 1

Areas to explore in fermented foods and health

• Open table in a new tab

Still, investigating the role of microbial metabolite production in a fermented food environment offers numerous intriguing yet understudied areas of research. Fermented foods lend themselves as simpler and tractable yet highly relevant models of microbe-microbe interactions compared to the human gut.76 Characterizing the fermented food metabolome and developing tools to better understand metabolite-microbe production dynamics within the fermented foods community has interesting applications for novel flavor and texture development. Transformation of unconventional substrates into familiar flavors can aid in sustainability efforts.238 In addition, with the growing interest in the gut-brain-axis research, the fermented food landscape offers a pool of understudied small molecules that might influence taste preference behavior,239,240,241,242 as well as novel compounds relevant to human health. Despite the exciting potential of fermented foods, research is still needed to understand the complexities.

AcknowledgmentsAuthor contributions

All authors developed the manuscript content and organization. E.B.C. wrote the manuscript and assembled figures. All authors read, edited, and commented on the manuscript.

Declaration of interests

The authors declare no competing interests.

References

1.

Marco, M.L. ∙ Sanders, M.E. ∙ Gänzle, M. ...

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on fermented foods

Nat. Rev. Gastroenterol. Hepatol. 2021; 18:196-208

Crossref

Scopus (300)

PubMed

Google Scholar

2.

Gänzle, M.

Fermented foods

Food Microbiology

ASM Press, 2019; 855-900

Crossref

Scopus (22)

Google Scholar

3.

Turnbaugh, P.J. ∙ Ley, R.E. ∙ Mahowald, M.A. ...

An obesity-associated gut microbiome with increased capacity for energy harvest

Nature. 2006; 444:1027-1031

Crossref

Scopus (9136)

PubMed

Google Scholar

4.

Sonnenburg, J.L. ∙ Bäckhed, F.

Diet–microbiota interactions as moderators of human metabolism

Nature. 2016; 535:56-64

Crossref

PubMed

Google Scholar

5.

Cabral, D.J. ∙ Penumutchu, S. ∙ Reinhart, E.M. ...

Microbial metabolism modulates antibiotic susceptibility within the murine gut microbiome

Cell Metab. 2019; 30:800-823.e7

Full Text

Full Text (PDF)

Scopus (63)

PubMed

Google Scholar

6.

Koppel, N. ∙ Maini Rekdal, V. ∙ Balskus, E.P.

Chemical transformation of xenobiotics by the human gut microbiota

Science. 2017; 356, eaag2770

Crossref

Scopus (565)

PubMed

Google Scholar

7.

Wu, W. ∙ Sun, M. ∙ Chen, F. ...

Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43

Mucosal Immunol. 2017; 10:946-956

Full Text

Full Text (PDF)

Scopus (303)

PubMed

Google Scholar

8.

Lavelle, A. ∙ Sokol, H.

Gut microbiota-derived metabolites as key actors in inflammatory bowel disease

Nat. Rev. Gastroenterol. Hepatol. 2020; 17:223-237

Crossref

Scopus (881)

PubMed

Google Scholar

9.

Caussy, C. ∙ Tripathi, A. ∙ Humphrey, G. ...

A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease

Nat. Commun. 2019; 10:1406

Crossref

Scopus (204)

PubMed

Google Scholar

10.

Kau, A.L. ∙ Ahern, P.P. ∙ Griffin, N.W. ...

Human nutrition, the gut microbiome and the immune system

Nature. 2011; 474:327-336

Crossref

Scopus (2003)

PubMed

Google Scholar

11.

Larraufie, P. ∙ Martin-Gallausiaux, C. ∙ Lapaque, N. ...

SCFAs strongly stimulate PYY production in human enteroendocrine cells

Sci. Rep. 2018; 8:74

Crossref

Scopus (231)

PubMed

Google Scholar

12.

Shepherd, E.S. ∙ DeLoache, W.C. ∙ Pruss, K.M. ...

An exclusive metabolic niche enables strain engraftment in the gut microbiota

Nature. 2018; 557:434-438

Crossref

Scopus (219)

PubMed

Google Scholar

13.

Zeng, X. ∙ Xing, X. ∙ Gupta, M. ...

Gut bacterial nutrient preferences quantified in vivo

Cell. 2022; 185:3441-3456.e19

Full Text

Full Text (PDF)

PubMed

Google Scholar

14.

David, L.A. ∙ Maurice, C.F. ∙ Carmody, R.N. ...

Diet rapidly and reproducibly alters the human gut microbiome

Nature. 2014; 505:559-563

Crossref

Scopus (6605)

PubMed

Google Scholar

15.

Fischer, C.N. ∙ Trautman, E.P. ∙ Crawford, J.M. ...

Metabolite exchange between microbiome members produces compounds that influence Drosophila behavior

eLife. 2017; 6, e18855

Crossref

Scopus (111)

Google Scholar

16.

Gribble, F.M. ∙ Reimann, F.

Enteroendocrine cells: chemosensors in the intestinal epithelium

Annu. Rev. Physiol. 2016; 78:277-299

Crossref

Scopus (401)

PubMed

Google Scholar

17.

Spivak, I. ∙ Fluhr, L. ∙ Elinav, E.

Local and systemic effects of microbiome-derived metabolites

EMBO Rep. 2022; 23, e55664

Crossref

Scopus (7)

PubMed

Google Scholar

18.

Vinderola, G. ∙ Sanders, M.E. ∙ Cunningham, M. ...

Frequently asked questions about the ISAPP postbiotic definition

Front. Microbiol. 2023; 14, 1324565

Google Scholar

19.

Guthrie, L. ∙ Spencer, S.P. ∙ Perelman, D. ...

Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes

Cell Host Microbe. 2022; 30:863-874.e4

Full Text

Full Text (PDF)

PubMed

Google Scholar

20.

Dunn, R.R. ∙ Wilson, J. ∙ Nichols, L.M. ...

ReviewVolume 36, Issue 4p684-701April 02, 2024Open Archive

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Our extended microbiome: The human-relevant metabolites and biology of fermented foods

Elisa B. Caffrey1 Send email to ecaffrey@stanford.edu ∙ Justin L. Sonnenburg1,2,3 Send email to justins2@stanford.edu ∙ Suzanne Devkota4,5 Send email to suzanne.devkota@cshs.org

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DOI: 10.1016/j.cmet.2024.03.007 External LinkAlso available on ScienceDirect External Link

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Summary

One of the key modes of microbial metabolism occurring in the gut microbiome is fermentation. This energy-yielding process transforms common macromolecules like polysaccharides and amino acids into a wide variety of chemicals, many of which are relevant to microbe-microbe and microbe-host interactions. Analogous transformations occur during the production of fermented foods, resulting in an abundance of bioactive metabolites. In foods, the products of fermentation can influence food safety and preservation, nutrient availability, and palatability and, once consumed, may impact immune and metabolic status, disease expression‎, and severity. Human signaling pathways perceive and respond to many of the currently known fermented food metabolites, though expansive chemical novelty remains to be defined. Here we discuss several aspects of fermented food-associated microbes and metabolites, including a condensed history, current understanding of their interactions with hosts and host-resident microbes, connections with commercial probiotics, and opportunities for future research on human health and disease and food sustainability.

Keywords

1. fermentation
2. fermented foods
3. metabolomics
4. gut microbiome
5. microbial metabolites

Introduction

In food, fermentation includes “foods made through desired microbial growth and enzymatic conversions of food components,”1 occurring in aerobic and anaerobic contexts. The food fermentation process (see “What are fermented foods?” section) depends upon the microbial community to metabolize nutrients,2 altering the substrate (i.e., food) and producing metabolites and other molecules that can impact taste, texture, safety, and nutritional composition, as well as signal to the host and gut microbiome.

While this type of food fermentation happens ex vivo, a comparable microbial metabolism occurs in the gastrointestinal (GI) tract. Research on the gut microbiome has highlighted the importance of microbiome-derived metabolites in mediating human health and disease.3,4,5,6,7,8,9 By applying the same framework developed to study metabolite-host interactions in the gut, we can better understand the effects of fermented food metabolism on human health, offering an unexplored additional source of human-relevant microbial metabolites. From the perspective of the gut microbiome, fermentation can be defined as a primary metabolic process occurring in the absence of oxygen, such as the microbial consumption of complex carbohydrates in the colon. Dietary compounds metabolized by the gut microbiome lead to production of energy and metabolites, small chemical compounds that can influence the structure of gut microbial communities and signal directly to the host via interaction with different cell types within the gut10,11 or signal peripherally following absorption into circulation. Nutrients exiting the stomach that are not absorbed by the host small intestine make their way to the distal small intestine and colon, providing a pool of dietary compounds that gut microbes can access and metabolize.

Microbial strains that are well-matched to incoming nutrients tend to outcompete other members of the community, resulting in changes in the overall composition of the microbial community.12,13 This can occur within days of a major dietary change.14 The metabolites produced during microbial fermentation in the gut are a direct product of microbes that are being fueled by nutrient inputs. These compounds provide an energy source for other microbes; impact the ecosystem chemistry (e.g., pH); directly signal to the host, further restructuring the microbial community; and/or enter host systemic circulation, broadening metabolite reach.10,15,16,17 Postbiotics refer to the molecules that microbes produce18 as opposed to substrates that promote the growth of gut microbes, known as prebiotics. In this framework, diet can be considered a source of nutrients for both host and microbes, as well as a source of precursors for metabolites produced during fermentation by the gut microbiome.

There is a growing appreciation that microbially produced metabolites have a mediating role in health and disease, as seen in type 2 diabetes (T2DM), inflammatory bowel diseases (IBDs), and metabolic-associated fatty liver disease.3,4,5,6,7,8,9 Evidence of the influence of microbial-derived metabolites primarily comes from mechanistic studies, where they may promote health and disease states, as well as in their use as diagnostics or biomarkers. Production of these metabolites is influenced by a vast array of factors including diet, medications, baseline gut microbiota composition, and genetics.19 Similarly, metabolites produced during food fermentation offer a novel pool of signaling compounds that can interact with the GI tract, acting directly and indirectly on the host, with the potential to be further metabolized.

Consumption of fermented foods expands the possible interactions in the gut through increased chemical diversity. By considering food fermentation as an “extended microbiome,”20 a term previously used to describe fermented foods by Dunn et al.,20 we can reframe our relationship to fermented foods and their role in human health. Important considerations include how the practice of fermentation has shaped human biology, how fermented food consumption impacts health directly and indirectly, and future applications of food fermentation in biomedicine and extending beyond health. This review focuses on the role of metabolites as key mediators in the diet-microbe-host landscape, presenting current and potential roles fermented food microbiota-derived metabolites play in human health. We also review the need for expanded foundational information, such as characterizing the microbial communities and molecules associated with the wide array of fermented foods consumed globally.

What are fermented foods?

With the fermented food market expected to grow by over half a billion dollars in the next 4 years,21 fermentation has been of increasing research interest. Numerous reviews have offered an extended explanation of fermented food production.1,2 Here, we offer a brief summary.

Fermented foods (also referred to as ferments or microbial foods) are foods transformed by microbial growth and enzymatic conversions.1 During fermentation, members of the microbial community, which can include bacteria, yeast, or filamentous fungi, compete for resources with strain-specific nutritional and growth-condition preferences, accompanied by secretion of metabolites such as organic acids and antimicrobial peptides22,23 to gain advantage over competitors. Most fermented food is produced for specific sensory qualities including taste and aroma, which result from the production of specific metabolites. Key to the fermentation process is encouraging the growth of microbes through the manipulation of extrinsic factors such as temperature, pH, salinity, and humidity.

Where are the microbes coming from?

The source of microbes in a fermented food can be spontaneous, from a starter culture, or through “back-slopping.” In spontaneous fermentation, microbes from the environment (e.g., the surface of the raw ingredient, the hands of the producer, the room, and the equipment used to make the fermented food) initiate fermentation.24 While the initial microbial community will be more diverse, the raw ingredient and environmental factors will select for specific members of the community to dominate.25 Use of a starter culture (e.g., selected strain or group of strains) in a pasteurized substrate allows for a reliable final profile of the fermented food, preventing competition between the native microbial community and the added starter community. Starter cultures are widely used in fermented dairy production like yogurt and cheeses.20 In addition, starters can be constructed of characterized and sequenced strains deliberately chosen based on the presence or absence of specific traits, for example, to minimize the presence of antibiotic resistance genes that might be transferable to resident gut microbes.26 When a portion of a previous fermented food is incorporated into a next batch, propagating the microbial community, the process is called back-slopping fermentation2 and is analogous to subculturing or serial passage of microbial cultures in the lab. Examples of back-slopping include sourdough bread and kombucha,2,27 where a higher abundance of a previously successful microbial community can be used to initiate fermentation, although the community itself might be poorly characterized.

Dominant microbes involved in fermentation have been largely characterized, but there remains a need for the continued characterization of microbes involved in fermentation: in particular, characterization of microbes at lower abundance, which might play a role in shaping the microbial community or contribute to the metabolite pool. In addition, while there is general consistency in microbes that will be most abundant at the final stages of fermentation, like Lactiplantibacillus plantarum in vegetable fermentation or S. thermophilus and L. bulgaricus in yogurt, their final relative abundance, as well as the presence and abundance of other microbes in the community, remain variable from batch to batch. In line with microbial heterogeneity between fermentation batches, metabolite production and abundance will also be variable.28 Ongoing work modeling microbiota and metabolite dynamics during fermented food community assembly will shed light on how extrinsic factors might be used to decrease product variability.24

What does it mean for a food to be fermented?

While there are broad categories of microbes that can be involved in the fermentation process (e.g., lactic acid bacteria, acetic acid bacteria, filamentous molds, and yeast), lactic acid fermenting microbes are one of the most common classes, seen in the fermentation of many vegetables, dairy, and grains (e.g., kimchi, yogurt, and injera). In lactic acid fermentation of vegetables, addition of salt and access to preferred carbohydrate nutrient sources promote growth of halophilic lactic acid bacteria (LAB), leading to early community dominance and secretion of antimicrobial peptides and organic acids (predominantly lactic acid), further enhancing growth.29,30,31 LAB outcompetes potential spoilage-associated microbes and competitors, excluding undesirable microbes from the final ferment. Secretion of protein hydrolases to enhance nutrient accessibility, shown primarily in mold fermentation microbes like Aspergillus oryzae and Rhizopus oryzae, not only promotes fungal growth but also plays an important role in enhanced palatability of the fermented food. Additional metabolites produced during this process play important roles in enhancing palatability and food safety and mediate microbe-microbe and microbe-host interactions. It is important to note that many non-fermented foods are produced to mimic the flavor and preservation of fermented foods (e.g., vinegar/salt brined pickles).1 Manufacturers may add viable microbes to pickled foods or pasteurized fermented foods at the end of production, attempting to recreate the living microbial content of raw fermented foods and enabling “probiotic” or “contains live microbes” label claims; in many cases the supplemented microbes are different strains than those associated with fermentation and may be spores and therefore not metabolically active. Microbial density of lactic acid ferments ranges widely across products and can reach 105–1010 CFU/g32 with the microbes producing and consuming metabolites during microbial growth. While addition of probiotic microbes to consumer-ready food products increases CFU count, fermentation (and the accompanying metabolite production) does not occur. Therefore, the simple presence of bacteria or fungi on an ingredient label does not necessarily mean it is a fermented product. For example, an olive brined in dilute lactic acid and salt with spores of a Bacillus species (distant relative of Lactobacillus that is able to form spores) added before sealing can create a shelf-stable product with highly reproducible flavor that mimics a lactic acid ferment and enables a claim of “contains live microbes.” However, such a product deviates significantly from a traditionally fermented olive. Data are lacking as to whether mimicking food fermentation by adding purified metabolites or live microbes has the same benefit, particularly when consuming microbes distinct from those that are typically found in fermented foods. Also, in the addition of probiotics (considered "dietary supplements") to food FDA draft guidelines recommend including the total weight of the added microbial mass and CFU of viable microbes, with no recommendation as to maximum allowed supplemented probiotic CFU or weight count.33 While estimates from the National Health and Nutrition Examination Survey (NHANES) data show there is a trending increase in consumption of foods containing live microbes in the American diet, estimates of CFUs or microbial type are still lacking.34 Characterizing the typical range of dietary microbe consumption and defining a healthy personalized range is necessary for the establishment of dietary recommendations and regulation of commercial products.35

Fermented foods: A brief history

While the earliest evidence of human engagement with food fermentation dates back to at least 14,000 years BCE,36 evolutionary genetics support a much longer relationship between humans and food-derived microbially produced metabolites. Roughly 10 million years ago, corresponding to the movement of our great ape ancestors from trees to the forest floor, evolution of the alcohol dehydrogenase class IV (ADH4) enzyme allowed our hominid ancestors to metabolize ethanol, likely a primary metabolite produced by yeast spontaneously fermenting fallen fruit.37 Over the course of human history, food fermentation has been practiced by most culinary traditions, dependent on substrate availability.20 The use of fermented ingredients is not uncommon in historical medicinal practices, with documented use of wine, doenjang (Korean fermented soybean paste), and garum (fermented fish sauce)38,39,40 for the treatment and prevention of ailments. The modern conceptualization of microbial foods as “health foods” stems from Élie Metchnikoff, who hypothesized Bacillus bulgarian (now Lactobacillus delbrueckii subsp. bulgaricus), which had been isolated from Bulgarian curdled milk referred to as “yahourth,” was responsible for the increased longevity observed in the Balkan population compared to other European populations. Work on the isolation and administration of this strain established probiotics as both a concept and a commercial product (Box 1). A revitalization of at-home fermentation production41 accompanied by the rise in the commercial fermented food market21 has focused on marketing fermented foods for “health” properties, although there is a lack of consensus on how and in what context health can be defined.35 Here we present the current understanding and limitation of the use of microbial foods for human health, focusing on the role of metabolites as microbe-host mediators and highlighting areas of future research.

Box 1

Fermented foods and probiotics

L. delbrueckii subsp. bulgaricus is one of the key starter strains used to make yogurt today42 and was also the first described probiotic,43 isolated from fermented dairy. The term probiotic refers to a well-defined and characterized live microorganism with demonstrated health benefits,1 which might be consumed in pure form (e.g., probiotic pill) or added to a food (e.g., probiotic yogurt). According to this definition, fermented foods made with spontaneous fermentation or through back-slopping do not fit the formal definition of probiotic unless the microbiome of the fermented food has been characterized and the strains are proven to exert health benefits. In commercial fermented food preparation, probiotic strains might be added into the yogurt once fermentation is complete, as with L. plantarum and L. rhamnosus,44 two strains also found in fermented foods,45 or many of the Bifidobacterium spp. strains that are not associated with food fermentation but rather were isolated from other sources such as infant feces.46,47

While probiotics have been extensively reviewed,48 success in trials is highly variable and appears dependent on a number of factors. A randomized, double-blind, placebo-controlled study looking at the impact of stomach acid on probiotic intervention showed that suppression of stomach acid production with proton pump inhibitors (PPIs) might enhance probiotic effectiveness, possibly via improved viability.49 More recently, a randomized controlled trial looking at the effects of probiotics on metabolic syndrome identified diet as a key differentiating factor between responders and non-responders, with non-responders having higher levels of serum glucose and insulin at the end of the intervention.50 Unexpectedly, total and added sugar, lactose, and sucrose intake was higher in the probiotic responders compared to non-responders. Further research is needed to better understand basic interactions between probiotics, diet, host gut microbiome, and host.

Current research points to metabolites and other probiotic products (sometimes commercially referred to as “postbiotics”) as key contributors to many of the benefits seen by probiotic consumption.18,51 While probiotics offer a characterized bacteria for a specific indication, in supplement form these products lack fermentation end products. Alternatively, fermented foods offer an extensive reservoir of potential postbiotics that can directly impact the microbiome, immunity, and enteroendocrine system.

The extended microbiome

Metabolites produced during fermentation provide a key role in the increased safety,52 nutrient availability,53,54,55,56,57,58,59,60,61,62,63,64 and enhanced gustatory qualities22,65,66 of fermented foods. Understanding how the microbial strains present combined with other factors, including salinity, pH, and temperature, contribute and influence metabolite production remains a necessary consideration when characterizing the final fermented product, particularly when it comes to food safety.

Enhancing food safety

Preserving food through fermentation is a reliable technique to enhance safety and stability over a prolonged period of time. During fermentation, metabolites produced during microbial competition for nutrients inhibit growth of competitors, concomitantly preventing growth of potential human pathogens. Production of various organic acids, primarily lactic or acetic acid, decrease the pH and create an inhospitable environment for food-borne pathogens like C. botulinum, L. monocytogenes, E. coli O157:H7, and S. flexneri.67,68,69 Secretion of antimicrobial compounds like bacteriocins, antibacterial peptides with both narrow and broad-spectrum activity, has been extensively studied in fermented food-associated LAB, including in kimchi, cheese, and fermented cereals,23,29,70,71 and shows high specific activity against known food pathogens.29 To date in the US, no cases of botulism have been reported in vegetable fermentation, mold-based fermentation, or dairy fermentation,72 with the rare cases being home-fermented meats, including beaver tail and uneviscerated fish, and tofu.73

Much of the insight into the mechanisms underlying the ecology of fermented foods has come from their use as a model microbial ecosystem. One example is the identification of novel antimicrobials that mediated microbe-microbe interactions,25,74,75 highlighting fermented foods as a potentially rich source of novel antimicrobials for medical application. More generally, the reduced microbial diversity in fermented foods compared to the gut microbiome provides improved tractability for exploring community assembly, transkingdom interactions, strain-diversity, and microbial evolution.76

Fermentation can also enhance food detoxification. Raw cassava, a starchy tuberous root native to South America and a staple food for over 500 million people,77 contains high levels of neurotoxic cyanogenic glycosides,78 which can be reduced by >70% through fermentation,79 with L. plantarum and Loigolactobacillus coryniformis believed to play a major role.80,81 Consumption of unprocessed cassava can lead to development of the irreversible neurological disorder konzo, which disproportionately affects rural areas in Africa.82 Gaining mechanistic insight into cassava detoxification would allow for improvement in food safety, with potential application to other foods.

Increasing nutrient availability and antioxidants

Fermented foods also have a documented history of use as nutrient supplements. James Cook, the British explorer, successfully prevented and treated scurvy among his crew by instructing them to consume 2 lb. of sauerkraut each a week, estimated to provide about 150 mg of ascorbic acid.53 However, these increased concentrations in nutrients might be specific to the microbial strains found in the ferment. Early work looking at prevention of scurvy in guinea pigs fed commercial sauerkraut found that two of the sauerkrauts successfully prevented scurvy while two other sauerkrauts did not. No difference was identified between the sauerkraut manufacturing conditions; however, microbial communities that might be involved in the observed differences were not investigated for potential differences.54 More recent studies support an increase in vitamins and nutrients in fermented foods compared to unfermented ingredients, including vitamins C, B2, B12, and K and folate.55,56,57,58,59,60,83 Additionally, release of encrypted bioactive components like polyphenol and flavonoid from tea leaves over the course of kombucha production increases antioxidant content of the drink.61 There is some rodent evidence pointing to host benefits following consumption of fermentation-driven enhanced nutrient bioavailability62,63; however, the chemical complexity combined with depletion of precursors (e.g., glucose) provides many confounders. Additional work is needed to isolate the effects of the wide array of relevant variables such as (1) diversity and variability in nutrients across fermented food; (2) the fermented food microbiota at a strain-specific level; and (3) elucidating factors, including host and microbiome genetics, that can impact nutrient absorption.

Flavor and taste

Fermentation is often practiced for its culinary use, where transformation of taste, smell, texture, and other sensory stimuli of the food during this metabolic process acts in synthesis to change the perceived flavor of the food. Spoilage is often associated with “off-flavors,” while novel flavors not typically associated with the starting ingredient are often a desired result of the fermentation process. For example, carbohydrate fermentation can result in the production of thiazoles and furfural, associated with nutty and almond-like flavors84,85 via sugar degradation and Maillard reaction pathways. Promotion of the Ehrlich pathway, an amino acid catabolic process, during fermentation can also lead to an increase in sulfur-containing, aromatic, and branched-chain volatiles like 2-phenylethanol, associated with a rose-like odor.30,86 Other metabolites like organic acids, flavonoids, and polyphenols can also contribute to the change in flavor of the final ferment.22,65 In addition, filamentous fungi can secrete hydrolases during fermentation,87 increasing simple amino acids and oligosaccharides and thus promoting umami and sweet taste sensation.

As expression‎ of sweet, bitter, and umami sensors is not limited to the oral cavity but expressed across the human GI tract,88 metabolites typically associated with flavor may play a role beyond the host gustatory system, particularly when coupled with nutrient absorption. Sensing of sweetness by T1R2/T1R3, a G protein-coupled receptor (GPCR) heterodimer expressed in enteroendocrine cells (EECs) in the human gut, can promote secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2).89,90,91 Activation of T1R2/T1R3 is not limited to sucrose but includes a variety of sweet-tasting stimuli including fructose and lactose, sweet amino acids such as glycine and d-tryptophan, sweet proteins such as monellin and thaumatin, and synthetic sweeteners such as aspartame and sucralose. Whether these ligands promote the same downstream T1R2/T1R3-mediated effects remains to be explored.92 Similarly, the GPCR T1R1/T1R3 mediates umami taste perception in the gut. The heterodimer is activated by L-amino acids such as monosodium glutamate (MSG; sodium L-glutamate) or L-cysteine and potentiated by inosine 5′-monophosphate (IMP) and other nucleotides. Activation of T1R1/T1R3 by MSG initiates peristaltic reflexes in rodent models, along with secretion of the pain-mediating neurotransmitter CGRP (calcitonin gene-related peptide) in the colon.93 CGRP receptor antagonists and anti-CGRP ligand monoclonal antibodies have more recently been approved for treatment and prevention of migraines.94

In humans, bitter taste perception is mediated by 25 putative members of the TAS2R (taste 2 receptor) GPCR family. Use of the bitterant caffeine has been shown to promote gastric acid secretion in the stomach through the TAS2R43 receptor,95 as well as lead to gut-derived serotonin secretion. Matured hop bitter acids (MHBAs), often added in the production of beer, have been shown to increase production of cholecystokinin (CCK) production by EECs,96 which plays a role in anorexigenic signaling and gastric emptying.97 Interestingly, olfactory receptors (ORs), a class of GPCRs typically found in the olfactory mucosa, have also been identified in the human gut. In purified form, the aromatic compound citronellal, also a volatile product of yeast geraniol fermentation in beer and wine production98,99,100 with an intense lemon scent, has been shown to stimulate GLP-1 secretion in both a human EEC line and mouse tissue across the small intestine.101 These examples illustrate the ability of molecules that trigger taste perception to impact host physiology. With growing interest in fermentation as a source of novel flavors,66 flavor-associated metabolites could impact important biological processes such as secretion of gut-derived peptides. Greater mechanistic insight into the roles metabolites produced during fermentation play both in perception of flavor and host biology is an exciting area for exploration, particularly focusing on how flavor-associated metabolites can modulate EECs (discussed later). In addition, inclusion of taste-preference and taste-perception surveys when conducting clinical fermented food research would aid in translatability and facilitate broader research into taste-associated compounds in food fermentation.

Food fermentation: Metabolite-host interactions

Consumption of a fermented food includes potential benefits beyond increased nutrient availability and food safety.58,64,45 In the gut, microbiome-derived metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids signal to the host through a variety of receptors, including transcription factors and GPCRs, playing a role in host incretin secretion, energy expenditure, and immune response.102,103,104,105,106 Insight into metabolite production in fermented foods will allow us to map similar metabolite-GPCR interactions, allowing deeper understanding of the role fermented food-associated microbes play in the host.

Metabolites and intestinal receptors

Gut microbiota-derived nicotinic acid,107 butyrate, and β-hydroxybutyrate produced in a ketoacidosis state108 can activate the hydroxycarboxylic acid receptor 2 (HCA2), expressed in a number of cell types, including the gut epithelium.109 Activation has been shown to have downstream anti-inflammatory effects,110,111 while chronic inflammation has been shown to downregulate HCA2 expression‎.112,113 HCA2 activation has also been shown to play a role in increasing bone density in weanling mice114 and suppresses NF-κB activation in colonic cell lines and in mouse colonic tissue.109 Additional metabolites, including hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3−PPA), activate HCA2.107 HA and 3-3−PPA are both products of hydroxycinnamate reduction in L. plantarum,115 commonly found in vegetable fermentation. While GPCRs are expressed across multiple cell and tissue types, their expression‎ on immune and EECs makes them of particular interest in understanding metabolite-host interaction in metabolic and immune disorders.

One of the indications of this fermented food metabolite-host relationship is the hydroxycarboxylic acid receptor 3 (HCA3). Described by Peters et al.,116 while most mammals express HCA1 and HCA2, only great apes (including humans) and siamang have an active HCA3, with humans exhibiting strongest activation. D-phenyllactic acid (D-PLA) is the only known HCA3 ligand117,118 and is produced by LAB. Measured in high concentrations in sauerkraut and up to 12.0–21.1 μg/mL in kimchi,119 it is elevated in the plasma following sauerkraut consumption.116 Lack of adequate animal models and currently no known HCA3 inhibitor has remained a challenge to the understanding of the biological relevance of HCA3.120 However, HCA3 expression‎ in human innate immune cells and adipose tissue lends to the hypothesis that HCA3 activation plays a role in host immuno-metabolism and energy storage.116 The extent to which consumption of other lactic acid-based ferments (including yogurt) can activate this receptor remains to be explored.28 Examining the effects of two primary fermented food metabolites, lactic and acetic acid, provides insight into how food fermentation can impact the host immune system. When produced by the host or gut microbiota, lactic acid activation of macrophage GPR81 reduces inflammatory responses in the colon.121,122 Oral administration of lactic acid increases microbiota-dependent regulatory T cells in the small intestine, promoting immune tolerance.123 Gut microbiota-derived acetate increases colonic IgA production and alters the capacity of the IgA pool to bind to specific members of the microbial community.124 Effects of dietary acetate have been primarily studied in disease models (Figure 1). The role of dietary acetate in healthy models remains an open area of investigation, with open questions similar to lactic acid. For both lactic and acetic acid, there is a need to (1) define the variability in organic acid production by microbial community and fermentation time point, (2) characterize the bioavailability of organic acids based on substrate type (sauerkraut compared to yogurt), and (3) gain further mechanistic insight into the downstream impact of organic acid consumption based on dosage and location of the metabolite-receptor interaction.

Figure 1 Fermented food microbes and metabolites can influence the immune system, endocrine system, and host gut microbiome

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Additional metabolites previously identified in fermented foods, including the host immune-modulating metabolite D-PLA, have been shown to reach μM plasma concentrations following ingestion of sauerkraut.116 A randomized human dietary intervention showed consumption of fermented foods leads to decreased markers of inflammation140 while promoting increased gut microbiome diversity when compared to a high-fiber-consuming cohort. In this study, specific serum metabolites, which may be derived from diet, microbiome, or host (or combinations thereof), correlated with specific aspects of the immune response. Expanded understanding of fermented food metabolites, their absorption, and interaction with human biology is the next step in characterizing ferment-immune interplay (Figure 2).

Figure 2 Metabolic paradigms of fermented food-derived metabolites

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EECs are hormone-producing cells accounting for about 1% of the gut epithelium. Acting at the interface between luminal content and host signaling, EECs produce more than 20 hormones in response to nutrient absorption. These hormones can signal systemically to the pancreas as well as the brain via vagal afferent neurons.175 While EECs can be stimulated directly by nutrients consumed, colonic EECs are also activated by bacterial SCFAs, notably butyrate and propionate, resulting from fiber fermentation. EEC-type distribution changes across the GI tract, with hormones like ghrelin and GIP primarily found in the upper small intestine and GLP-1 and peptide YY (PYY) primarily found in the colon,16 resulting in region-specific effects.129,176,177,178 Specific changes in gut colonization status, such as the absence of a microbiota (germ-free mice) or administration of a probiotic (Limosilactobacillus reuteri), have shown to increase GLP-1 levels, highlighting a role for microbial signaling in incretin regulations (reviewed in Arora et al.178). Recently, Akkermansia muciniphila has been shown to secrete a GLP-1-inducing metabolite, resulting in a reduction of a high-fat-diet-induced metabolic defects in mice.179 In conventional mice, PYY-positive EEC numbers increase in the colon in the presence of SCFAs via an FFA2-dependent pathway, reflected by an increase in circulating PYY, an enteroendocrine anorectic hormone.180 In humans, a study in individuals with diabetes consuming fermentable fibers for 84 days, with hemoglobin A1c (HbA1c) as primary endpoint, showed that those in the fiber arm resulted in significant reduction of HbA1c and fasting blood glucose at the end of the study. The authors found this was due to an increase in butyrate-producing bacteria and measured increases in butyrate levels resulting in significantly increased blood levels of GLP-1 and PYY over time.181 Another human study found that direct delivery of the SCFA propionate bound to inulin successfully delivered the propionate to the colon, resulting in significantly increased PYY and GLP-1 240 min after consumption of the oral propionate. Six months of daily supplementation resulted in attenuated weight gain and reduced intrahepatic lipids.182 Just as metabolites produced by the gut microbiota can influence host biology, metabolites produced during food fermentation can have similar interactions. The diversity of metabolites, many of which are likely to be distinct from those produced by gut-resident microbes, and interactions with microbes and host receptors in the small intestine likely produce an array of biological effects remain to be defined.

Ghrelin-secreting EECs also express GPR81, where lactate binding inhibits secretion of this “hunger hormone.”146 Unlike GLP-1-producing cells, which are primarily located in the colon, ghrelin-producing cells are primarily located in the stomach and duodenum, where they are more likely to interact with fermented food-derived lactic acid, with downstream effects on hunger signaling and metabolism. Additionally, mapping fermented food metabolites to GPCR receptors, particularly the number of orphan GPCRs,183 would allow for potential identification of novel GPCR-ligand pairings, expanding the development of a mechanistic framework of microbe-host interactions2 and allowing for a targeted exploration of downstream effects.

Fermented foods in human disease

The rise in health claims about fermented foods is not matched by an increase in clinical evidence. The few current studies are primarily focused on assessing the impact of fermented food on healthy individuals,23,140 with few studies looking at the role of fermented foods in patients with health conditions. Early data from irritable bowel syndrome (IBS)184,185 and metabolic diseases186,187,188,189 (including T2DM and obesity) offer examples of how fermented foods can improve human health through altering nutrient accessibility and impacting the human microbiome. These positive outcomes highlight the need for a greater understanding of the fermented food metabolome landscape to pursue molecular mechanistic mediators.

Meta-analyses of observational studies support a role of fermented dairy intake for the decreased risk of T2DM and cardiovascular disease.186,187,188,189 However, human clinical trials looking at the risk and prevention of these diseases in the context of fermented food consumption are lacking, with the strongest current evidence coming from animal models.190 A recent study on yogurt consumption in obese mouse models identified branched-chain hydroxy acids (BCHAs) produced during LAB-driven yogurt fermentation can supplement host BCHAs and improve metabolic parameters, including improved glucose tolerance and resistance to high-fat, high-sucrose diet-induced obesity. The effects appear to be driven by production of three hyodeoxycholic acids, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, and alpha-hydroxyisovalerate, produced by the gut microbiome.191

Kimchi consumption has also been studied for its impact on health, but few clinical trials have looked at the impact of consumption on metabolic disease. A small crossover clinical trial in obese patients reported significant decreases in body fat and improved metabolic markers.192 A follow-up crossover clinical trial followed prediabetic participants over the course of a 16-week period, reporting a decrease in insulin resistance and increased insulin sensitivity during the period of 10-day fermented kimchi consumption compared to 1-day fermented (defined as “fresh”) kimchi.193 Insight into how fermentation-derived metabolites impact secretion of incretin hormones like GLP-1 is an important step in understanding the mechanistic implications of fermented food consumption. Incorporating measurements of the foods’ differences in chemical composition, patient incretin hormones, insulin, and blood glucose in future clinical trials would greatly aid the understanding and translatability of laboratory work on fermented food metabolite-induced responses. There remains a clear need for randomized human clinical trials and mechanistic interrogation into how the fermented food microbiome and its metabolites interact with the host, including the resident microbial landscape.

While exploring fermented foods for health benefits remains an exciting frontier, there are examples where metabolites produced during fermentation can lead to negative health consequences in sensitive health populations. Biogenic amines are amino acid derivatives produced during fermentation that can include tyramine, histamine, cadaverine, and putrescine, with tyramine and histamine being of particular interest. Even small amounts of dietary tyramine (8–10 mg) can lead to hypertensive episodes in the presence of the antidepressant class monoamine oxidase inhibitors,194 with occasional fatalities reported.195 Dietary tyramine is increased in ferments like fish sauce, sauerkraut, and aged cheeses, but abundance can vary widely depending on food and fermentation time196; thus, patient dietary recommendations need to consider sensitivity, food type, serving size, and drug interactions. While tyramine production is enhanced by increased sodium content in the ferment, a variety of approaches have been applied to limit tyramine production during fermentation. For example, successful tyramine reduction was achieved with the addition of tyramine- or tyrosine-oxidizing LAB in a micro-cheese model.197 Similarly, certain LAB associated with food fermentation have been described as histamine producers, including Lentilactobacillus parabuchneri, Lentilactobacillus buchneri, and Oenococcus oeni,198,199,200,201 primarily with proteinaceous substrates like in dairy and meat ferments. While recommendations for a low-histamine diet show high efficacy for histamine hypersensitivity, fermented foods show a wide range of histamine abundance, with length of fermentation time, storage, and cooking method all influencing histamine abundance at ingestion.202 Mechanistic understanding of histamine production, characterization of extrinsic factors impacting production, and rapid biogenic amine detection methods are all necessary both from a clinical and a consumer perspective. It is likely that extending such detection methods to other biomolecules will aid in quality control and inform health claims, particularly as potential benefits of fermented foods on other physiological aspects are explored further.

Previous studies have shown associations of fermented food or pickled vegetable (terms used interchangeably in the studies; see “What are fermented foods section”) intake and esophageal and stomach cancer.203,204,205,206

These concerns are related to retrospective studies where the quality and contamination of the fermented foods was not tested, and many confounders exist. For example, one widely cited study published in 1980 focused on the preval‎ence of esophageal cancer in Northern Chinese populations,203 with data from 1959 to 1970. The study found a positive correlation between “pickled vegetable” consumption (likely fermented based on literature description) and esophageal cancer risk, but due to long fermentation storage period, the authors note that much of the food became covered with a white mold. This association was also seen in regions with higher consumption of laozao, a fermented sweet grain dish. However, samples were found to have high fungal contamination, including Aspergillus flavus, associated with increased production of carcinogenic compounds.207,208,209,210,211 In addition, enzymatic activity of other molds in the sample is hypothesized to allow for synthesis of N-nitroso compounds, associated with higher cancer risk.212,213 With the exception of dairy fermented products that are primarily produced using well-defined cultures, vegetable ferments and kombuchas are largely driven by spontaneous fermentation or uncharacterized microbial communities, respectively. However, fermented food found at grocery stores is required to meet hazard analysis critical control point (HACCP) compliance and go through rigorous safety testing before being commercially available, significantly decreasing the risk of contamination by toxin-producing microbes. Conversely, several studies have shown fermented food intake is associated with no increased risk or a decreased risk from certain cancers and diabetes.186,188,189,214,215,216,217,218 Future prospective studies with better characterization and documentation of types of fermented foods consumed are required to understand if such concerns are valid.

Food fermentation: Microbe-microbe interactions

Composition of an individual’s gut microbiome is influenced by host genetics and lifestyle, including diet, medical practices, and environment. Studies comparing gut microbial composition across different lifestyles note decreasing gut microbiome diversity in industrialized populations, believed to be driven by factors associated with an industrialized lifestyle including antibiotic overuse, high-fat and high-sugar diet, and decreases in breastfeeding.219 Not only does immigration to an industrialized environment from a non-industrialized environment lead to a decrease in microbial diversity,220 but this decrease in microbial diversity compounds over time and over the course of generations.219,220,221,222 Within industrialized populations, more diverse gut microbiomes are a conserved metric associated with resistance to Western-associated diseases, such as T2DM, heart disease, and colorectal cancer.223,224,225 Understanding how diet can increase an individual’s microbiome diversity is an active topic of research in the gut microbiome field. Fermented food consumption appears to be a promising tool in gut microbiome reconstruction.

Fermented foods and the human gut microbiome

Dietary nutrients and host-derived metabolites, including lactate and 3-hydroxybutyric acid, can impact the human gut microbiome, shifting microbial composition with downstream implications for host health from metabolic disease to immune status.13,19,177 Similarly, fermented food consumption appears to have important effects on the gut microbiome. The American Gut Project, a citizen science project, reported subtle but significant shifts in the beta-diversity and taxa of fermented food consumers compared to non-consumers across 6,811 participants. Of interest, fermented food consumers had an increase in conjugated linoleic acid (CLA) producers and fecal CLA,226 fatty acid metabolites that activate the nuclear receptor PPAR-γ227,228 to exert beneficial health effects on a number of conditions including IBD and T2DM.

A randomized clinical trial comparing high fermented food consumption to high fiber consumption showed fermented food consumption increased gut microbiome diversity compared to baseline, with alterations in the gut microbiome composition that were durable beyond the trial period.140 Nine amplicon sequence variants (ASVs) in the Firmicutes phylum increased across high fermented food compared to high fiber, including four members of the Lachnospiraceae family, two Ruminococcaceae, and one Streptococcaceae. This increase in gut microbiome diversity was not observed in the fiber-consuming groups. This trend in increased microbiome diversity has been further supported by a more recent randomized control trial comparing gut microbial composition following 6 weeks of fermented vegetables, pickled vegetables, or no vegetables.229 Not only was there an increase in gut microbiota diversity from baseline to completion of the study in the fermented vegetable group, but microbiota diversity did not change in the pickled vegetable or non-vegetable consumer group. Remaining questions include whether this increased diversity is mediated via host immune effects, live microbes in the fermented foods, metabolites alone, or other macromolecules and how durable the response is after cessation of fermented food consumption.

Interestingly, the majority of microbes responsible for the increase in diversity were not from the ferments and were likely either acquired from the environment or present in the hosts before the intervention but below detection limits. Whether fermented foods may act as a source of microbes to increase diversity or lead to compositional shifts that promote incorporation of transient microbes remains to be understood. Very few studies have assessed human microbiota composition before, during, and after fermented food consumption.140,229 A study comparing mother-infant strain sharing in a rural Ethiopian cohort identified two microbes from injera (Fructilactobacillus sanfranciscensis and Lactiplantibacillus xiangfangensis), a locally produced teff flour ferment, as contributors to diversity in maternal-infant cohorts.230 However, due to the popularity of injera consumption, whether these microbes were transient or had become incorporated into the gut microbiome could not be determined.

Comparison of LAB genomes from fermented foods to the human microbiome reveals distinct sequences, supporting the idea that fermented foods are a transient source of LAB for the gut microbiome. Differences in LAB species identified across Western and non-Western gut microbiome populations appear to reflect lifestyle.231 Understanding which LABs are transient or engrafted stable members of the gut community should be aided by more investigation and improved genomic resolution. Early work on engraftment into the gut microbial community shows successful incorporation of microbes is largely dependent on method of administration, diet, absence of similar strains (i.e., open niche space), and host genetics.12,232,233,234 Shifts in the gut microbiome and host environment following fermented food consumption likely play an additional role in engraftment success, offering additional complexity and opportunity for targeted incorporation of missing key members. Reports of enteric pathogens and antimicrobial resistance genes within commercial fermented foods highlight the importance of vigilance in monitoring the microbes that inhabit fermented foods.235

While current evidence shows an exciting role for fermented foods in modulation of the gut microbiome community, future clinical work would shine a light on a number of open questions: (1) understanding the role of specific fermented foods, including duration and conditions of fermentation and storage, in modulating the gut microbiome; (2) clinical trials across a number of cohorts, including those with clinical needs, to understand the limitations in the impact on the gut microbiome community; and (3) defining how differences in microbial load or pasteurization (or other post-fermentation processing) or cooking status might impact the gut microbial community.

Future directions and conclusions

While fermented foods offer potential for modulation of human health and disease through microbes and metabolites, expanded scientific understanding is needed at multiple levels. Foundational insight into the basic biology of fermented foods, such as the strains, genomes, metabolites, ecological succession, and stability of microbes over time is critical information to enable pursuing connections to human health. In addition, use of tools for secondary metabolite predictions, such as antiSMASH236 and MicrobeMASST,237 and application of both targeted and untargeted metabolomics will contribute greatly to the identification of metabolites at the interface of microbe-microbe and metabolite-host interaction. Such data will aid mechanistic studies that can employ model systems such as cell culture and animal models. The field of gut microbiome science serves as a useful template for advancing such investigation, and many of the experimental approaches are directly applicable. At the same time, human studies are needed to delineate which fermented foods at what levels of intake impact what biology in which cohort or population. These studies should include well-designed and carefully executed dietary interventions in healthy populations to survey changes in biology and physiology such as immune and metabolic parameters.

Additionally, clinical trials in patient cohorts targeting specific outcomes are necessary to support the incorporation of fermented food, or its components, into current medical practice; integral to medical use is the need for advanced types of quality control for the fermented food product to ensure safety and that specific bioactive components are present at required levels and no off-target effects are introduced. Whether there is a future for the prescription of medical fermented foods with certified microbial or metabolite abundances, particularly for groups with health vulnerabilities, remains an open area of exploration but will require a number of basic mechanistic questions to be addressed.

With unhealthy food driving many common diseases in the industrialized world, incorporation of fermented foods will also serve to replace commonly consumed foods that are incompatible with long-term health (e.g., ultra-processed, high glycemic). Fermented foods may serve as a gateway for consumers and patients to more broadly understand the power of diet to directly impact health. Several key points (Table 1) make fermented foods a candidate in catalyzing a movement toward expanded food-based health care. The ability of individuals to easily implement fermentation in their own kitchen enables economical production, engagement with food, and ability to customize to personal preferences; importantly, variation between at-home and commercial production of fermented foods remains to be explored, including heterogeneity in microbe and metabolite production between commercially available fermented foods. The wide variety of fermented foods also presents a wide range to meet the needs of people with different dietary restrictions and taste preferences. Indeed, the molecules produced during fermentation that dictate texture and flavor are likely to also play biological roles in many cases.

AreaStatus of fermentation researchEstablishedFuture area of research

General benefits of fermentation	• Enhanced food safety through organic acid and antimicrobial production; decreased abundance of potential pathogens23,29,67,70,71,72,73 • Increased nutrient availability (e.g., antioxidants and vitamins)53,54,55,56,57,58,59,60,61,62,63,64 • Substrate detoxification (e.g., cassava)78,79,80,82	• Fermented food microbiota strain-specific roles in nutrient enhancement, bioavailability, detoxification, flavor, and other final fermented food properties • Host factors affecting fermented food-derived nutrient absorption • Factors affecting microbial community development in starter and wild fermentation • Characterization of toxin production on novel substrates, including development of at-home food fermentation testing tools • Identification of commercially or medically useful fermented food products, e.g., antimicrobials to combat the rise of fungal pathogens and antibiotic resistance
Food fermentation microbiome-host interactions	• Consumption associated with trends toward decreases in markers of inflammation in healthy cohorts121,122,123,124,140	• Identification of metabolites produced during the food fermentation process across various substrates, including use of targeted and untargeted mass spectrometry, including LC- and GC-MS for broad compound discovery • Assessment of live microbe-host interaction compared to metabolite-host interaction, particularly in disease phenotypes • Characterization of metabolite-host interaction, including mechanism on host immune and enteroendocrine systems
Food fermentation microbiome-host microbe interactions	• Fermented food consumption increases gut microbiome diversity116,206,210	• Identification of source of microorganisms in spontaneously fermented foods • Role of fermented food consumption in engraftment • Role of fermented food microbe or metabolite in gut microbial community composition and metabolism
Beyond fermented food-gut interactions	• Effective models for the study of microbe-microbe interactions25,74,75,76	• Role of fermented food metabolites in gut-brain-axis signaling, particularly a role in satiety and hunger signaling • Application of fermentation for promotion of sustainability efforts238

Table 1

Areas to explore in fermented foods and health

• Open table in a new tab

Still, investigating the role of microbial metabolite production in a fermented food environment offers numerous intriguing yet understudied areas of research. Fermented foods lend themselves as simpler and tractable yet highly relevant models of microbe-microbe interactions compared to the human gut.76 Characterizing the fermented food metabolome and developing tools to better understand metabolite-microbe production dynamics within the fermented foods community has interesting applications for novel flavor and texture development. Transformation of unconventional substrates into familiar flavors can aid in sustainability efforts.238 In addition, with the growing interest in the gut-brain-axis research, the fermented food landscape offers a pool of understudied small molecules that might influence taste preference behavior,239,240,241,242 as well as novel compounds relevant to human health. Despite the exciting potential of fermented foods, research is still needed to understand the complexities.

AcknowledgmentsAuthor contributions

All authors developed the manuscript content and organization. E.B.C. wrote the manuscript and assembled figures. All authors read, edited, and commented on the manuscript.

Declaration of interests

The authors declare no competing interests.

References

1.

Marco, M.L. ∙ Sanders, M.E. ∙ Gänzle, M. ...

The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on fermented foods

Nat. Rev. Gastroenterol. Hepatol. 2021; 18:196-208

Crossref

Scopus (300)

PubMed

Google Scholar

2.

Gänzle, M.

Fermented foods

Food Microbiology

ASM Press, 2019; 855-900

Crossref

Scopus (22)

Google Scholar

3.

Turnbaugh, P.J. ∙ Ley, R.E. ∙ Mahowald, M.A. ...

An obesity-associated gut microbiome with increased capacity for energy harvest

Nature. 2006; 444:1027-1031

Crossref

Scopus (9136)

PubMed

Google Scholar

4.

Sonnenburg, J.L. ∙ Bäckhed, F.

Diet–microbiota interactions as moderators of human metabolism

Nature. 2016; 535:56-64

Crossref

PubMed

Google Scholar

5.

Cabral, D.J. ∙ Penumutchu, S. ∙ Reinhart, E.M. ...

Microbial metabolism modulates antibiotic susceptibility within the murine gut microbiome

Cell Metab. 2019; 30:800-823.e7

Full Text

Full Text (PDF)

Scopus (63)

PubMed

Google Scholar

6.

Koppel, N. ∙ Maini Rekdal, V. ∙ Balskus, E.P.

Chemical transformation of xenobiotics by the human gut microbiota

Science. 2017; 356, eaag2770

Crossref

Scopus (565)

PubMed

Google Scholar

7.

Wu, W. ∙ Sun, M. ∙ Chen, F. ...

Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43

Mucosal Immunol. 2017; 10:946-956

Full Text

Full Text (PDF)

Scopus (303)

PubMed

Google Scholar

8.

Lavelle, A. ∙ Sokol, H.

Gut microbiota-derived metabolites as key actors in inflammatory bowel disease

Nat. Rev. Gastroenterol. Hepatol. 2020; 17:223-237

Crossref

Scopus (881)

PubMed

Google Scholar

9.

Caussy, C. ∙ Tripathi, A. ∙ Humphrey, G. ...

A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease

Nat. Commun. 2019; 10:1406

Crossref

Scopus (204)

PubMed

Google Scholar

10.

Kau, A.L. ∙ Ahern, P.P. ∙ Griffin, N.W. ...

Human nutrition, the gut microbiome and the immune system

Nature. 2011; 474:327-336

Crossref

Scopus (2003)

PubMed

Google Scholar

11.

Larraufie, P. ∙ Martin-Gallausiaux, C. ∙ Lapaque, N. ...

SCFAs strongly stimulate PYY production in human enteroendocrine cells

Sci. Rep. 2018; 8:74

Crossref

Scopus (231)

PubMed

Google Scholar

12.

Shepherd, E.S. ∙ DeLoache, W.C. ∙ Pruss, K.M. ...

An exclusive metabolic niche enables strain engraftment in the gut microbiota

Nature. 2018; 557:434-438

Crossref

Scopus (219)

PubMed

Google Scholar

13.

Zeng, X. ∙ Xing, X. ∙ Gupta, M. ...

Gut bacterial nutrient preferences quantified in vivo

Cell. 2022; 185:3441-3456.e19

Full Text

Full Text (PDF)

PubMed

Google Scholar

14.

David, L.A. ∙ Maurice, C.F. ∙ Carmody, R.N. ...

Diet rapidly and reproducibly alters the human gut microbiome

Nature. 2014; 505:559-563

Crossref

Scopus (6605)

PubMed

Google Scholar

15.

Fischer, C.N. ∙ Trautman, E.P. ∙ Crawford, J.M. ...

Metabolite exchange between microbiome members produces compounds that influence Drosophila behavior

eLife. 2017; 6, e18855

Crossref

Scopus (111)

Google Scholar

16.

Gribble, F.M. ∙ Reimann, F.

Enteroendocrine cells: chemosensors in the intestinal epithelium

Annu. Rev. Physiol. 2016; 78:277-299

Crossref

Scopus (401)

PubMed

Google Scholar

17.

Spivak, I. ∙ Fluhr, L. ∙ Elinav, E.

Local and systemic effects of microbiome-derived metabolites

EMBO Rep. 2022; 23, e55664

Crossref

Scopus (7)

PubMed

Google Scholar

18.

Vinderola, G. ∙ Sanders, M.E. ∙ Cunningham, M. ...

Frequently asked questions about the ISAPP postbiotic definition

Front. Microbiol. 2023; 14, 1324565

Google Scholar

19.

Guthrie, L. ∙ Spencer, S.P. ∙ Perelman, D. ...

Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes

Cell Host Microbe. 2022; 30:863-874.e4

Full Text

Full Text (PDF)

PubMed

Google Scholar

20.

Dunn, R.R. ∙ Wilson, J. ∙ Nichols, L.M. ...