Re: 발효음식이 인체건강에 미치는 기전 2023 네이처 리뷰!!

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발효음식 인체건강 2023 네이처.pdf

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Abstract

Although fermentation probably originally developed as a means of preserving food substrates, many fermented foods (FFs), and components therein, are thought to have a beneficial effect on various aspects of human health, and gastrointestinal health in particular. It is important that any such perceived benefits are underpinned by rigorous scientific research to understand the associated mechanisms of action. Here, we review in vitro, ex vivo and in vivo studies that have provided insights into the ways in which the specific food components, including FF microorganisms and a variety of bioactives, can contribute to health-promoting activities. More specifically, we draw on representative examples of FFs to discuss the mechanisms through which functional components are produced or enriched during fermentation (such as bioactive peptides and exopolysaccharides), potentially toxic or harmful compounds (such as phytic acid, mycotoxins and lactose) are removed from the food substrate, and how the introduction of fermentation-associated live or dead microorganisms, or components thereof, to the gut can convey health benefits. These studies, combined with a deeper understanding of the microbial composition of a wider variety of modern and traditional FFs, can facilitate the future optimization of FFs, and associated microorganisms, to retain and maximize beneficial effects in the gut.

Key points

Fermented foods provide a unique combination of beneficial microorganisms and bioactive compounds that can contribute to gastrointestinal health in a variety of ways.

• A better understanding of fermented foods, their associated gastrointestinal health benefits and the underlying mechanisms has benefited from a greater appreciation of the unique biological and chemical composition of diferent fermented foods.

• Fermentation can be utilized to reduce or even remove undesirable compounds present in food substrates, such as FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) or gluten, to aid patients with intolerances that influence the gut.

• Fermented foods represent a safe way for increased microbial exposure with a view to improving gut health and potentially reducing the risk of chronic gut disease.

• Further research into fermented foods, especially involving randomized and controlled human trials, is required.

초록

발효는

원래 식품 기질을 보존하기 위한 수단으로 발전했을 가능성이 높지만,

발효 식품(FF)과 그 구성 성분은

인간 건강,

특히 위장 건강의 다양한 측면에서 유익한 효과를 가질 것으로 여겨집니다.

이러한 인식된 이점이

엄격한 과학적 연구를 통해 뒷받침되어

관련 작용 기전을 이해하는 것이 중요합니다.

여기서는 발효 식품의 특정 성분,

특히 FF 미생물과 다양한 생리활성 물질이 건강 증진 활동에 기여할 수 있는 방법을 밝혀준

in vitro, ex vivo, in vivo 연구를 검토합니다.

보다 구체적으로, 우리는

대표적인 FF 사례를 들어

발효 중 기능적 성분(예: 생리활성 펩타이드 및 외부 다당류)이 생성되거나 농축되는 메커니즘,

식품 기질에서 제거되는 잠재적으로 독성적이거나 유해한 화합물(예: 피틱산, 마이코톡신, 락토오스),

그리고 발효 관련 살아 있거나 죽은 미생물 또는 그 구성 성분이 장에 도입되어

건강상의 이점을 제공할 수 있는 방식을 논의합니다.

이러한 연구와 현대 및 전통 FF의 미생물 조성에 대한 더 깊은 이해를 결합하면,

장에서 유익한 효과를 유지하고 극대화하기 위해

FF와 관련 미생물을 미래에 최적화할 수 있습니다.

주요 요점

• 발효 식품은 유익한 미생물과 생리활성 화합물의 독특한 조합을 제공하여 다양한 방식으로 위장 건강에 기여할 수 있습니다.
• 발효 식품의 고유한 생물학적 및 화학적 조성에 대한 더 깊은 이해는 발효 식품, 그와 관련된 위장 건강 이점, 그리고 그 기저 메커니즘에 대한 이해를 증진시켰습니다.
• 발효는 식품 기질에 존재하는 바람직하지 않은 화합물(예: FODMAPs 또는 글루텐)을 줄이거나 제거하여 장에 영향을 미치는 불내성 환자에게 도움을 줄 수 있습니다.
• 발효 식품은 장 건강을 개선하고 만성 장 질환 위험을 줄일 가능성을 고려할 때, 증가된 미생물 노출을 위한 안전한 방법입니다.
• 발효 식품에 대한 추가 연구, 특히 무작위 대조 인간 시험이 필요합니다.

Introduction

Fermented foods (FFs) and beverages have been staples of the human diet for millennia, with the natural fermentation of dairy products having been recorded as far back as 10,000 BCE1 . During this long history, food fermentation has been employed primarily for the preservation, and associated safety, of foods. Food fermentations can be different from energy conservation fermentative metabolism, in which fermentation can be viewed as “an ATP-generating process in which organic compounds act as both donors and acceptors of electrons”2 . Indeed, the first connection between yeasts and anaerobic ethanolic fermentation was made by Louis Pasteur in 1856, with the first ‘health claim’ for a FF being proposed by Elie Metchnikoff much later in 1910, when he attributed good health and longevity to the consumption of fermented milk3 . Since then, considerable advances have been made in the study of FFs, the microorganisms and bioactives they contain, the factors that influence this composition, and the various effects, positive, neutral and occasionally negative, of FFs on health and disease4 . In 2021, FFs were defined as “foods made through desired microbial growth and enzymatic conversions of food components”5 (Box 1). This definition emphasizes the key requirement for microbial activity in the formation of FFs, while differentiating FF from food spoilage, and is sufficiently broad to be inclusive of the wide range of fermentative processes. Indeed, food fermentations are diverse depending on the microbes involved and their primary metabolites, with some examples being acetic acid bacteria (AAB) and acetic acid, lactic acid bacteria (LAB) and lactic acid, Propionibacterium and propionic acid, yeasts and alcohol and/or carbon dioxide, and Bacillus and moulds and ammonia and/or fatty acid (Fig. 1; Table 1).

서론

발효 식품(FFs)과 음료는

수천 년 동안 인류 식단의 주요 식품이었으며,

유제품의 자연 발효는 기원전 10,000년 전까지 거슬러 올라가는 기록이 있습니다.

이 오랜 역사 동안 식품 발효는

주로 식품의 보존 및 그와 관련된 안전성을 위해 사용되었습니다. 

식품 발효는

'유기 화합물이 전자의 공여체이자 수용체로 작용하는 ATP 생성 과정'으로 볼 수 있는

에너지 보존 발효 대사와는 다를 수 있습니다. 

실제로

효모와 혐기성 에탄올 발효 사이의 첫 연관성은

1856년 루이 파스퇴르에 의해 밝혀졌으며,

발효 식품에 대한 최초의 '건강 효능 주장'은

그보다 훨씬 뒤인 1910년 엘리 메치니코프가

발효유 섭취가 건강과 장수의 비결이라고 주장하면서 제기되었습니다. 

그 이후로 발효 식품, 그 안에 포함된 미생물과 생리활성 물질,

그 구성에 영향을 미치는 요인들,

그리고 발효 식품이 건강과 질병에 미치는 다양한 긍정적, 중립적,

때로는 부정적인 영향에 대한 연구에서 상당한 진전이 있었습니다. 

2021년,

발효 식품은

'바람직한 미생물 성장과 식품 성분의 효소적 전환을 통해 만들어진 식품'으로

정의되었습니다(박스 1).

이 정의는

발효 식품 형성에 있어 미생물 활동이 핵심적인 요구사항임을 강조하는 동시에

식품 부패와는 구별하며,

광범위한 발효 과정을 포괄할 수 있을 만큼 충분히 넓은 의미를 가집니다.

실제로

식품 발효는 관련된 미생물과 그 주요 대사산물에 따라 다양하며,

그 예로는 아세트산균(AAB)과 아세트산, 유산균(LAB)과 젖산, 프로피오니박테리움과 프로피온산,

효모와 알코올 및/또는 이산화탄소,

그리고 바실러스균 및 곰팡이와 암모니아 및/또는 지방산 등이

있습니다(그림 1; 표 1).

To yield these distinct metabolites and microbiota, food fermentations are performed using a wide6 variety of food substrates, including dairy, vegetables, legumes, fruits and meats and fish (reviewed elsewhere4,7–14). The list of FFs arising out of a wide range of microbiota–substrate combinations is substantial. However, despite their traditional consumption in most cultures has led to a gradual reduction in the diversity of FFs and dietary microorganisms consumed over the past century15. Over the past decade, FFs have regained popularity, at least partially due to a renewed appreciation of their health-promoting potential6,11. The acquisition of evidence for such health benefits has been aided by the emergence of -omics-based technologies, particularly high-throughput DNA sequencing, which has enabled a better understanding of the microbial composition of these foods and their metabolic potential, as well as their influence on the human gut microbiota. Genomic and metagenomic data have highlighted that FF microbiomes (or ‘fermentomes’) (Box 1) are taxonomically diverse (even within the same FFs), enriched in potentially health-associated gene clusters (PHAGCs) (Box 1), an important reservoir for potentially novel probiotic microorganisms, and an important source of LABs in the gut16,17. These advances, combined with increasing numbers of in vivo studies, have led to new insights relating to the mechanisms through which FFs might positively modulate the gut microbiota and gut–brain axis18, and positively affect cardiovascular19, immune20 and metabolic health21, among others. In this Review, we focus on the mechanisms underpinning the gut health-promoting potential of FFs. To this end, we discuss benefits conferred through enzymatic actions (during and after fermentation), production of novel compounds during fermentation including bioactive peptides, diverse organic acids and exopolysaccharides, and enrichment of various bioactive compounds including vitamins, minerals and amino acids, among others. Furthermore, we discuss the removal of undesirable compounds from foods through fermentation. Notably, to elucidate the possible mechanisms through which FFs can modulate health, we focus on selected examples for which there is strong evidence, and addressing the potential health benefits of all FFs and their components is beyond the scope of this Review (reviewed elsewhere22). Finally, we provide a perspective on the future of FF research, including the need for more clinical trials, the importance of overcoming regulatory challenges and the merits of including FFs in global dietary guidelines. worldwide in some form, the large-scale industrialization of food production, particularly in Western countries.

이러한 독특한 대사산물과 미생물 군집을 생성하기 위해 식품 발효는

유제품, 채소, 콩류, 과일, 육류 및 어류 등

매우 다양한 식품 기질을 사용하여 수행됩니다(다른 문헌에서 검토됨).

광범위한 미생물-기질 조합에서 비롯되는 발효 식품의 목록은

상당합니다.

하지만

대부분의 문화권에서 전통적으로 섭취해왔음에도 불구하고,

특히 서구 국가에서의 대규모 식품 생산 산업화로 인해

지난 세기 동안 섭취하는 발효 식품과 식이 미생물의 다양성은 점차 감소했습니다.

지난 10년 동안 발효 식품은

건강 증진 잠재력에 대한 재평가에 힘입어

부분적으로나마 인기를 되찾았습니다.

이러한 건강상의 이점에 대한 증거 확보는

오믹스(-omics) 기반 기술,

특히 대량 DNA 시퀀싱의 등장으로 도움을 받았습니다.

이를 통해 이들

식품의 미생물 구성과 대사 잠재력,

그리고 인체 장내 미생물총에 미치는 영향에 대한 더 나은 이해가 가능해졌습니다.

유전체 및 메타유전체 데이터는

발효 식품 마이크로바이옴(또는 '발효체(fermentomes)')(박스 1)이

분류학적으로 다양하고(같은 발효 식품 내에서도),

잠재적으로 건강과 관련된 유전자 클러스터(PHAGCs)(박스 1)가 풍부하며,

잠재적으로 새로운 프로바이오틱 미생물의 중요한 저장소이자,

장내 유산균(LABs)의 중요한 공급원이라는 점을 밝혔습니다.

이러한 발전은 증가하는 생체 내 연구와 결합하여,

발효 식품이 장내 미생물총과 장-뇌 축을 긍정적으로 조절하고,

심혈관, 면역, 대사 건강 등에 긍정적인 영향을 미칠 수 있는 메커니즘에 대한

새로운 통찰로 이어졌습니다.

본 총설에서는

발효 식품의 장 건강 증진 잠재력을 뒷받침하는 메커니즘에 중점을 둡니다.

이를 위해 우리는

(발효 중 및 발효 후의) 효소 작용을 통해 얻는 이점,

생리활성 펩타이드,

다양한 유기산 및 엑소폴리사카라이드를 포함한 발효 중 새로운 화합물의 생산,

그리고 비타민, 미네랄, 아미노산 등

다양한 생리활성 화합물의 강화에 대해 논의합니다.

'

bioactive peptides,

diverse organic acids and exopolysaccharides, and

enrichment of various bioactive compounds including vitamins, minerals and amino acids,

among others.

더 나아가,

발효를 통해 식품에서 바람직하지 않은 화합물을 제거하는 것에 대해서도

논의합니다.

특히,

발효 식품이 건강을 조절할 수 있는 가능한 메커니즘을 규명하기 위해,

우리는 강력한 증거가 있는 일부 사례에 초점을 맞추며,

모든 발효 식품과 그 구성 요소의 잠재적인 건강상의 이점을 다루는 것은

본 총설의 범위를 벗어납니다(다른 문헌에서 검토됨).

마지막으로,

우리는 더 많은 임상 시험의 필요성,

규제 문제 극복의 중요성,

그리고 전 세계 식단 지침에 발효 식품을 포함하는 것의 장점을 포함하여

발효 식품 연구의 미래에 대한 전망을 제공합니다.

Fermentation-associated functional compounds

Fermentation can result in the generation and/or enrichment of a diverse range of bioactive compounds, several of which have been associated with beneficial effects across various gastrointestinal conditions5,6 , based on human studies or inferred from in vitro or animal studies. A cross-section of these bioactives are discussed here.

발효와 관련된 기능성 화합물

발효는 다양한 생물활성 화합물의 생성 및/또는 농도 증가를 유발할 수 있으며, 이 중 일부는 인간 연구 또는 체외 또는 동물 연구에서 추론된 결과에 따라 다양한 소화기 질환에 유익한 효과를 나타내는 것으로 알려져 있습니다5,6. 이 중 일부 생물활성 화합물에 대해 논의합니다.

Enzymatic actions

Microbial and endogenous enzymatic action within the food substrate during fermentation (that is, in situ) can lead to the hydrolysis of proteins, polysaccharides and fats, that in turn can improve digestibility and nutrient bioavailability5,23 (Fig. 1). For example, cereals usually have low protein digestibility and/or a suboptimal amino acid profile due to the presence of antinutritive factors and complex structure of the proteins therein24. Fermentation can improve protein digestibility in cereals, as well as other substrates, by reducing inhibitors of digestive enzymes (such as trypsin or chymotrypsin), removing compounds (such as tannins) that promote crosslinking, and producing microbial proteases that partially degrade and release proteins from the matrix25–28. High levels of tannins can contribute to an unpleasant taste or astringent feel in food matrices; tannases in LAB such as Lactiplantibacillusplantarum have been shown to transform tannins (for example, gallotannins to gallic acid) during fermentation, leading to reduced astringency29–31. Fermentation of milk by LAB also improves the digestibility of milk proteins, whereby proteolytic enzymes and peptidases produced by LAB increase the bioavailability of amino acids in yogurt32. Additionally, fermentation-associated changes in the food matrix can lead to improved functionality of endogenous enzymes in the food substrates that in turn can have health benefits. For example, in the case of wheat or rye sourdough fermentation, a decrease in pH brought about by fermentative LAB can activate cereal xylanases (at pH ~3.5–5.5) that leads to an increase in the water-soluble fraction of arabinoxylans, which have been shown to have prebiotic effects in the human gut23,33–36. Similarly, wheat and rye sourdough fermentations can create optimal pH conditions for endogenous aspartic proteases (pH 3–4.5) and carboxypeptidases (pH 4–6), often responsible for primary proteolysis, that can degrade up to 5% of cereal proteins37. Yet another example of improved endogenous protease action is observed during protein degradation in meat fermentations, in which some tissue-based enzymes such as cathepsins can show increased activity at an acidic pH38. Notably, the strain-specific and species-specific protease activity of lactobacilli can produce a diverse array of peptides and amino acids during cereal fermentations, often at increased concentrations, which have demonstrated potential antioxidant, antihypertensive or cancer-preventing attributes in in vitro and animal models (reviewed elsewhere39,40).

효소 작용

발효 과정에서 식품 기질 내 미생물 및 내인성 효소의 작용(즉, in situ)은 

단백질, 다당류 및 지방의 가수분해를 유발할 수 있으며, 

이는 소화율과 영양소 생체 이용률을 향상시킬 수 있습니다5,23(그림 1). 

예를 들어, 

통곡물(시리얼)은 

항영양 인자의 존재와 단백질의 복잡한 구조로 인해 

단백질 소화율이 낮거나 아미노산 프로필이 최적화되지 않은 경우가 많습니다24. 

cereals usually have low protein digestibility and/or

a suboptimal amino acid profile due to the presence of antinutritive factors and

complex structure of the proteins therein

발효는 

곡물 및 기타 기질에서 단백질 소화율을 개선할 수 있습니다. 

이는 소화 효소 억제제(예: 트립신 또는 키모트립신)를 감소시키고, 

교차 결합을 촉진하는 화합물(예: 탄닌)을 제거하며, 

미생물 단백질 분해효소를 생성하여 

단백질을 매트릭스에서 부분적으로 분해하고 방출하기 때문입니다25–28. 

타닌의 높은 함량은 

식품 매트릭스에서 불쾌한 맛이나 떫은 느낌을 유발할 수 있습니다. 

LAB(유산균)인 Lactiplantibacillus plantarum에 존재하는 타나아제는 

발효 과정에서 타닌(예: 갈로타닌을 갈산으로 전환)을 변환시켜 

떫은 맛을 감소시키는 것으로 알려져 있습니다29–31. 

LAB에 의한 우유 발효는 

우유 단백질의 소화성을 향상시키며, 

LAB이 생성하는 단백질 분해 효소와 펩티다제가 요거트 내 

아미노산의 생체 이용률을 증가시킵니다32. 

또한 발효 관련 식품 매트릭스 변화는 

식품 기질 내 내인성 효소의 기능성을 향상시켜 

건강에 이로운 효과를 가져올 수 있습니다. 

예를 들어, 

밀이나 라이 밀 발효 과정에서 LAB에 의한 발효로 인한 pH 감소는 

곡물 엑스라나제(pH 약 3.5–5.5)를 활성화시켜 

아라비노엑스란의 수용성 분율을 증가시킵니다. 

이는 인간 장에서 

프리바이오틱 효과를 나타내는 것으로 알려져 있습니다23,33–36. 

同様に, 

밀과 라이 sourdough 발효는 

내인성 아스파르트산 프로테아제(pH 3–4.5)와 

카르복시펩티다제(pH 4–6)의 최적 pH 조건을 생성하며, 

이는 주로 초기 단백질 분해에 관여하여 

곡물 단백질의 최대 5%를 분해할 수 있습니다37. 

또 다른 예로는 

육류 발효 과정에서 단백질 분해 시 일부 조직 기반 효소인 카테프신 등이 

산성 pH에서 활성이 증가하는 현상이 관찰됩니다38. 

특히, 락토바실러스의 균주 특이적 및 종 특이적 프로테아제 활성은 

곡물 발효 과정에서 다양한 펩타이드와 아미노산을 생성하며, 이

는 체외 및 동물 모델에서 항산화, 항고혈압 또는 암 예방 특성을 보여줍니다(기타 문헌에서 검토됨³⁹,⁴⁰).

Fermentative lactobacilli-induced acidification and accumulation of thiols results in an increased solubility of gluten proteins in sourdough, making them more susceptible to the combined degradative action of endogenous and microbial proteolytic enzymes23,37; this step in turn provides benefits to patients with coeliac disease in whom gluten consumption can trigger an autoimmune response (discussed below in ‘Fermentative removal of undesirable compounds: Gluten’). Additionally, fermentation-associated removal of compounds such as lactose in dairy and fructans in wheat improve tolerability of these foodstuffs (discussed below in ‘Fermentative removal of undesirable compounds’)5,41. Lipolytic release of free fatty acids (primary polyunsaturated fatty acids) during the fermentation of fish has also been demonstrated42. The benefits of FF-associated enzymatic activities in the gut are evident among individuals deficient in the enzyme lactase, which is required to break down lactose into glucose and galactose, through consumption of fermented dairy, particularly yogurt. The observed beneficial effect of yogurt in reducing gastrointestinal symptoms related to lactose malabsorption is attributed to the removal of lactose from the dairy matrix during fermentation as well as delivery of the lactase enzyme (β-galactosidase) to the gut by fermenting microorganisms43 (Fig. 1) (discussed below in ‘Fermentative removal of undesirable compounds: Lactose’). Other enzymes have also been shown to have potential ex situ health benefits, such as the serine fibrinolytic enzyme nattokinase, which is enriched during natto fermentation. Indeed, nattokinase exhibits antithrombotic, anticoagulant and fibrinolytic properties in vitro and in animal models that might potentially play a part in benefiting cardiovascular health44,45. Notably, the fibrinolytic activity of nattokinase is four to six times that of plasmin, as observed both in vitro and in vivo in rats, and is achieved through a combination of direct fibrin dissolution, increased conversion of pro-urokinase to urokinase, increased activation of tissue plasminogen activator and cleavage of plasminogen activator inhibitor 1 (refs. 46,47). The potential clinical impact of nattokinase on hypertension and as a fibrinolytic agent has been demonstrated through several animal and human studies44,48–50. Rodent studies have demonstrated that nattokinase can translocate across the murine intestinal tract, and the enzyme can be detected in blood plasma and serum from animals and humans48,51. Further research, however, is needed to understand the precise mechanisms of action of nattokinase in humans, which remain unclear, along with methods to protect nattokinase through gastric transit where the enzyme undergoes a loss of stability due to the gastric pH52. Interestingly, natto-rich diets have also been reported to significantly reduce liver cholesterol and triglyceride levels (P < 0.01) and positively modulate the gut microbiota (significantly higher levels of Lachnospiraceae and caecal short-chain fatty acids (SCFAs) (P < 0.05) in the natto-treated group) in mouse models53. Additionally, Bacillus natto, the bacterium that produces nattokinase, has been reported to positively modulate the human gut microbiota54, particularly by increasing the abundance of intestinal bifidobacteria, as well as improving faecal frequency and bulk55.

발효성 락토바실러스에 의한 산성화와 티올의 축적은 

사워도우에서 글루텐 단백질의 용해도를 증가시켜 

내인성 및 미생물 단백질 분해 효소의 복합적 분해 작용에 더 취약하게 만듭니다23,37; 

이 단계는 

글루텐 섭취로 자가 면역 반응이 유발될 수 있는 

셀리악 병 환자에게 유익합니다(아래 '발효에 의한 바람직하지 않은 화합물의 제거: 글루텐'에서 설명). 

또한, 

발효에 의해 유제품의 유당 및 밀의 프럭탄과 같은 화합물이 제거되면 

이러한 식품의 내약성이 향상됩니다(아래 '발효에 의한 바람직하지 않은 화합물의 제거'에서 설명). 

어류 발효 과정에서 

지방 분해에 의한 자유 지방산(주로 다불포화 지방산)의 방출도 보고되었습니다42. 

유당 분해 효소(lactase)가 결핍된 개인에서 발효 유제품, 

특히 요거트 섭취를 통해 장 내 FF 관련 효소 활성의 이점이 명확히 나타납니다. 

요거트가 

유당 흡수 장애와 관련된 위장관 증상을 완화하는 데 미치는 유익한 효과는 

발효 과정에서 유제품 매트릭스에서 유당이 제거되는 것뿐만 아니라 

발효 미생물에 의해 장으로 전달되는 락타아제 효소(β-갈락토시다제)에 기인합니다43(그림 1)

(아래 '발효를 통한 유해 물질 제거: 유당'에서 논의됨). 

다른 효소들도 

체외에서 건강에 유익한 잠재력을 보여주었습니다. 

예를 들어, 

나토 발효 과정에서 풍부해지는 

세린 섬유소 용해 효소 나토키나제는 

체외 및 동물 모델에서 항혈전, 항응고, 섬유소 용해 특성을 나타내며, 

심혈관 건강에 유익한 역할을 할 수 있습니다44,45. 

특히, 나토키나제의 섬유소 용해 활성은 

체외 및 쥐 모델에서 플라스민보다 4~6배 높으며, 

이는 직접적인 섬유소 용해, 프로-우로키나제의 우로키나제로의 전환 증가, 

조직 플라스미노겐 활성화제의 활성화 증가, 

플라스미노겐 활성화 억제제 1의 분해 등을 통해 달성됩니다(참조 46,47). 

나토키나제의 고혈압 치료 및 섬유소 용해제로서의 잠재적 임상적 영향은 

여러 동물 및 인간 연구를 통해 입증되었습니다44,48–50. 

쥐 실험에서는 

나토키나제가 쥐의 장관을 통해 이동할 수 있으며, 

동물과 인간에서 혈장 및 혈청에서 해당 효소가 검출되었습니다48,51. 

그러나 

인간에서의 나토키나제의 정확한 작용 메커니즘은 여전히 불분명하며, 

위산에 의해 효소의 안정성이 손실되는 

위 통과 과정에서 나토키나제를 보호하는 방법도 추가 연구가 필요합니다52. 

흥미롭게도, 

나토가 풍부한 식단은 

쥐 모델에서 간 콜레스테롤 및 트리글리세라이드 수치를 유의미하게 감소시켰으며(P < 0.01), 

장 미생물군을 긍정적으로 조절했습니다

(나토 처리 그룹에서 Lachnospiraceae 및 결장 단쇄 지방산(SCFAs) 수치가 유의미하게 높음(P < 0.05))53. 

또한, 나토키나제를 생성하는 박테리아인 Bacillus natto는 

인간 장내 미생물군집을 긍정적으로 조절한다는 보고가 있으며, 

특히 장내 비피도박테리아의 풍부도를 증가시키고 배변 빈도와 양을 개선하는 것으로 나타났습니다55.

Bioactive peptides and amino acids

Bioactive peptides may be defined as a group of low molecular weight peptides or protein fragments that are usually 3–20 amino acid residues in length, and demonstrate beneficial physiological effects56. During fermentation, pH changes and proteolytic activity of microorganisms can lead to the denaturation of proteins, which lose their original conformation and can release small bioactive peptides buried in their structure5,57. Several peptides of interest have been isolated from a diverse range of FFs6 with several in vitro and animal studies indicating potentially beneficial functions including antihypertensive, antioxidant, antimicrobial, immunomodulatory and antithrombotic activities (reviewed elsewhere58,59). Some of the most well-characterized bioactive peptides from FFs are angiotensin-converting enzyme (ACE) inhibitors (2–12 amino acid residues in length, in which the presence of tyrosine, phenylalanine, tryptophan, proline, lysine, isoleucine, valine, leucine and arginine can influence ACE-binding ability60,61), with trilactopeptides VPP and IPP generated in yogurt shown to protect against hypertension in clinical trials62–64. Other well-characterized bioactive peptides include those with antioxidant properties, which can potentially exert their effects through several mechanisms including activation of the KEAP1–NRF2 signalling pathway as demonstrated in multiple in vitro studies59,65.

생물활성 펩타이드 및 아미노산

생체활성 펩타이드란 

일반적으로 3~20개의 아미노산 잔기로 구성된 저분자량 펩타이드 

또는 단백질 조각으로, 

유익한 생리적 효과를 나타내는 물질로 정의될 수 있습니다56. 

Bioactive peptides may be defined as a group of

low molecular weight peptides or

protein fragments that are usually

3–20 amino acid residues in length,

and demonstrate beneficial physiological effects

발효 과정에서 pH 변화와 미생물의 단백질 분해 활성은 

단백질의 변성을 유발할 수 있으며, 

이로 인해 단백질은 원래 구조를 잃고 

구조 내에 숨겨진 작은 생물활성 펩타이드를 방출할 수 있습니다5,57. 

다양한 FFs에서 여러 관심 대상 펩타이드가 분리되었으며, 

체외 및 동물 실험을 통해 항고혈압, 항산화, 항균, 면역조절, 항혈전 활성 등 

잠재적으로 유익한 기능이 보고되었습니다(기타 문헌에서 검토됨58,59). 

FF에서 가장 잘 특성화된 생물활성 펩타이드 중 일부는 

안지오텐신 전환 효소(ACE) 억제제입니다

(2–12 아미노산 잔기 길이로, 

티로신, 페닐알라닌, 트립토판, 프로린, 라이신, 이소류신, 발린, 류신 및 아르기닌의 존재가 

ACE 결합 능력을 영향을 미칠 수 있음60,61)이며, 

요거트에서 생성된 트릴락토펩티드 VPP와 IPP는 

임상 시험에서 고혈압 예방 효과를 보여주었습니다62–64. 

다른 잘 알려진 생물활성 펩타이드에는 

항산화 특성을 가진 펩타이드가 포함되며, 

이는 KEAP1–NRF2 신호전달 경로의 활성화 등을 통해 효과를 발휘할 수 있다는 것이 

여러 체외 연구에서 입증되었습니다59,65.

Other widely studied fermentation-derived peptides are bacteriocins, which are ribosomally synthesized antimicrobial peptides (AMPs) that are antagonistic towards other microorganisms66,67. Bacteriocins can be classified into three primary groups: lantibiotics (class I bacteriocins, <5 kDa in size; contain post-translation modifications and unusual residues), non-lanthionine-containing bacteriocins (class II bacteriocins, <10 kDa; limited post-translational modifications) and non-bacteriocin lytic proteins (class III, >30 kDa; heat-labile antimicrobial proteins)66,68. Many of these antimicrobial compounds are active against pathogens, including those situated in the gut of animals and humans69. Indeed, bacteriocins are important contributors to microorganism–microorganism and host–microorganism interactions in the human gut, effected through in situ inhibition or displacement of competing pathogens, mediation of communication between gut microorganisms as a signalling peptide, and assisting in colonization of bacteriocin producers70,71 (Fig. 1). Additionally, bacteriocins contribute to improving the integrity of the intestinal barrier (for example, by augmenting tight junctions between epithelial cells), inducing secretion of AMPs from the gut epithelium as well as regulation of inflammation through activation of the ERK–MAPK, PKC and PKA pathways72–75 (Fig. 1).

발효에서 유래한 다른 널리 연구된 펩타이드에는 

박테리오신(bacteriocins)이 포함되며, 

이는 리보솜에서 합성되는 항미생물 펩타이드(AMPs)로 

다른 미생물에 대해 항적성을 나타냅니다66,67. 

박테리오신은 

세 가지 주요 그룹으로 분류됩니다: 

란티바이오틱스(1형 박테리오신, 크기 <5 kDa; 포스트트랜스레이셔널 변형 및 이례적인 잔기 포함), 

란티오닌 비함유 박테리오신(2형 박테리오신, 크기 <10 kDa; 번역 후 변형이 제한적), 및 

비박테리오신 용해 단백질(제3류, 분자량 >30 kDa; 열에 불안정한 항균 단백질)로 분류됩니다66,68. 

이 중 많은 항균 화합물은 

동물과 인간의 장내에 존재하는 병원체 포함해 다양한 병원체에 활성을 보입니다69. 

실제로 박테리오신은 

인간 장내에서 미생물 간 및 호스트-미생물 상호작용에 중요한 역할을 하며, 

경쟁적 병원체의 현장 억제 또는 대체, 장내 미생물 간 신호 전달 펩타이드로서의 역할, 

박테리오신 생산자의 정착을 돕는 방식으로 작용합니다70,71 (그림 1). 

또한 박테리오신은 

장 장벽의 무결성을 향상시키는 데 기여합니다(예: 상피 세포 간의 밀접 결합을 강화함으로써), 

장 상피에서 AMP의 분비를 유도하며, E

RK–MAPK, PKC 및 PKA 경로의 활성화 통해 

염증 조절을 조절합니다72–75 (그림 1).

Fig. 1 | Mechanisms of action for bioactive components in fermented foods. The figure provides a snapshot of various key pathways through which diverse fermented food (FF) components delivered to the gut influence intestinal and indeed systemic health. Fermentation results in an increase in bioavailability and absorption for polyphenols, minerals and amino acids, with various amino acids and derivatives delivered through FFs acting as neurotransmitters and/or immunotransmitters. Bioactive peptides and beneficial microorganisms in FFs can inhibit intestinal pathogen growth and colonization. Organic acids, exopolysaccharides and short-chain fatty acids (SCFAs) (delivered directly or produced in situ in the gut by gut microorganisms) contribute to stimulation of the immune system, maintenance of gut barrier integrity, pathogen inhibition and reduction of inflammation. Enzymes produced during fermentation can break down complex molecules into simpler units that improve digestibility and uptake of the corresponding food matrices. Additionally, enzymes such as β-galactosidase (or lactase) delivered through microbial components of FFs improve digestibility of lactose, particularly in lactase-deficient individuals. ECC, enteroendocrine cell; EEC, enterochromaffin cell; LPS, lipopolysaccharide; MAMPs, microorganism-associated molecular patterns; MUC, mucin; NF-κB, nuclear factor κ-B; PRR, pattern recognition receptor; sIgA, secretory IgA; TH1, T helper 1 cell; TH2, T helper 2 cell; TLR, toll-like receptor; Treg, regulatory T cell.

Other non-bacteriocin, FF-borne peptides can affect gut health by promoting overexpression‎ of certain host genes, including AMPs and mucin-producing genes. For example, pyroglutamyl peptides (usually three to six amino acids long), which are encountered commonly in Japanese FFs such as miso and shoyu76,77, and have been shown to provide protection against experimentally induced hepatitis78, colitis and/or a disrupted gut microbiota79 in animals. This is achieved through an increase in mucin production due to the upregulation of the Muc2 and Muc4 genes in goblet cells, an elevation of lysozyme and defensin 5 expression‎ in Paneth cells80, and an increased expression‎ of other AMPs in the intestine76. FFs additionally can contain and/or generate precursor amino acids (such as l-tryptophan and l-glutamic acid) and derivatives that might have neuroactive and/or immunomodulatory functions6,81–86. For example, cocoa has been reported to contain serotonin, dopamine and noradrenaline at concentrations of 0.4–3.3 μg/g, 1.0 μg/g and 8.2 μg/g, respectively87,88. Additionally, yeasts have been shown to synthesize kynurenine, kynurenic acid and melatonin in FFs such as beer, bread and red wine89–92. LAB have been demonstrated to be important producers of γ-aminobutyric acid (GABA), with several LAB FFs enriched with GABA93. Research is ongoing regarding the whole gamut of neurochemicals that can be produced by LAB in FF matrices, with several LAB strains isolated from FFs able to produce GABA, tyramine, histamine and tryptamine (reviewed in detail elsewhere94). The various concentrations at which these neuroactive substances might be present in different FFs have been discussed elsewhere94–96. Neurochemicals delivered as such could influence the vagus nerve, which connects the gut with the brain, and/or elicit localized and systemic responses to modulate sleep, mood, stress, anxiety, pain and hunger97–100 (Fig. 1). FFs have additionally also been implicated in neuroprotection and to have potential cognitive benefits101. Notably, in vitro studies have shown that several amino acids and derivatives including serotonin, GABA, kynurenine and dopamine, among others, have a key role as immunotransmitter molecules102–104 (reviewed in refs. 105,106). A mix of in vitro and in vivo studies have also indicated that amino acids such as glutamine, arginine and sulfur-containing amino acids, often enriched in FFs22, may help to maintain intestinal integrity, growth and function, as well as modulate inflammatory cytokine secretion, T cell function and IgA secretion in the gut107.

Notably, some FFs can contain biogenic amines, which are organic, nitrogenous compounds formed primarily through microbial decarboxylation of amino acids during the fermentation process108. Importantly, some biogenic amines, such as histamine, can have toxicological consequences at higher concentrations108,109. The intake of FFs with high biogenic amine loads (such as aged cheese and meats), coupled with inadequate detoxification by monoamine and diamine oxidases, in the gut of individuals with a genetic susceptibility can lead to biogenic amines entering the systemic circulation, and excessive gastric secretion, adrenaline and noradrenaline release, migraine, and elevated blood sugar and blood pressure, among other effects110. Additionally, in vitro studies have demonstrated that secondary amines such as putrescine and cadaverine can be cytotoxic111 and react with nitrite to form carcinogenic nitrosamines112,113, whilst studies in ex vivo models have shown that tyramine can promote adherence of pathogenic microorganisms (such as Escherichia coli 0157:H7 in the intestinal mucosa)114.

Vitamins and minerals

Fermentation can lead to the biosynthesis and consequent increase in concentrations of various vitamins, amino acids and cofactors that could affect health at the gastrointestinal and/or systemic levels; this aspect is often a strain-dependent feature of FFs6 . Under specific conditions, high levels of folate and riboflavin (vitamin B2) concentrations have been reported for fermented dairy and cereal products115–118. The vitamin B complex has a myriad of important roles in systemic and gut health119, with studies in rodent models implicating riboflavin deficiency in intestinal crypt hypertrophy, reduced villus number120,121, and interruptions in crypt bifurcation and intestinal cell proliferation122,123. Additionally, an enrichment of cobalamin (vitamin B12) concentration has been reported in fermented cereals, dairy and soy124–126; cobalamin deficiency can cause a reduction in intestinal barrier function and villus to crypt ratio, as shown in rodent models and humans, respectively127,128. Studies have also revealed higher total vitamin K (menaquinone) concentrations and increased diversity of menaquinone forms in fermented dairy substrates, particularly in fermented cheeses, natto, kimchi, kefir and Chinese soybean pastes, compared with non-fermented substrates129–132. Vitamin K has various roles in systemic and gut health, including suppression of colonic tumour development, improvement of intestinal integrity and inhibition of gut pathogens, among others133. FFs and beverages, such as fermented olives, sauerkraut, tarhana and boza, are frequently rich in minerals134. Notably, the minerals present in many substrates, and plant-based substrates in particular, have poor bioavailability due to the formation of complexes with non-digestible matter, such as complex carbohydrates135. The production of enzymes such as maltases, α-amylases, hemicellulases and phytases during fermentation leads to the breakdown of complex structures and the inhibition of antinutritive compounds, which in turn improves the bioavailability of minerals such as zinc, calcium, iron and magnesium136,137 (Fig. 1). The fermentation-associated reduction in pH in food matrices as well as in the gut lumen, also facilitates greater mineral solubility and increased passive uptake, particularly of iron and calcium138–140 (Fig. 1). Notably, dairy products are in general rich in calcium, with, for example, yogurt allowing a high degree of absorption and retention of the mineral141. Although there is no evidence that yogurt enables better absorption of calcium than milk and other dairy products141,142, as noted already it is well tolerated by lactasedeficient individuals and therefore is an important source of calcium for such individuals142. Calcium absorption from yogurt is attributed to the presence of casein-derived phosphopeptides and amino acids as well as lactose in dairy products, which stimulates passive diffusion or active transport of the mineral141.

Organic acids

Several FFs are formed through fermentation energy conservation metabolism, whereas others can be products of respiratory metabolism (such as lactic acid fermentation carried out by LAB; reviewed in relation to FFs in refs. 5,143,144). Indeed, LAB and other bacteria can carry out saccharolytic fermentation of carbohydrates or sugars through several metabolic pathways whereby pyruvate (a universal intermediate metabolite) can be further metabolized to produce a diversity of organic acids144–146. Production of organic acids leads to acidification of the FF matrix and inhibits the growth of pathogens or spoilage-inducing microorganisms14. Lactic acid is one of the most frequently produced organic acids in LAB fermentations with concentrations that can reach 1% in such fermentations6 (Table 1). In vitro studies have shown that lactate can significantly reduce (P < 0.05) the generation of reactive oxygen species in intestinal enterocytes, thereby altering the redox status of these cells, as well as act as a source of SCFA synthesis for the gut microbiota147–149. d-Phenyllactic acid (PLA), a natural bacterial agonist, is frequently found in a range of LAB-fermented foodstuffs including kimchi (PLA levels 12.0–21.1 μg/ml during early stages of fermentation and 4.8–9.5 μg/ml during later stages150) and sauerkraut150. In vitro and in vivo experiments have additionally shown that PLA can modulate immune responses through HCA3 receptors in monocytes, promote anti-inflammatory processes and stimulate adipocytes in a HCA3-dependent manner151.

Other FFs, such as table olives, are rich in oleic acid, which has been reported to provide a protective effect against colon cancer in humans152–154. Notably, kombucha fermentation produces various organic acids and derivatives that can exert beneficial effects on health (organic acid levels for a representative black tea kombucha: glucuronic acid (1.58 g/l), gluconic acid (70.11 g/l), d-saccharic acid-1,4-lactone (5.23 g/l), ascorbic acid (0.70 g/l), acetic acid (11.15 g/l) and succinic acid (3.05 g/l)155). For example, gluconic acid, produced by kombucha AAB during the fermentation process, can selectively support the growth of Bifidobacterium spp. in the gut156,157. Other important organic acids produced include lactic and glucuronic acid157,158, with, in the latter case, glucuronic acid catabolism by specific kombucha bacteria resulting in the production of d-glucaric acid and its lactone derivative d-glucaro-1,4-lactone (or d-saccharic acid-1,4-lactone or DSL)11,159,160, which inhibit oxidative stress, diabetes-induced renal damage161 and paracetamol-induced hepatic injury162 in rodent models. Importantly, in vitro studies have shown that DSL is a potent competitive inhibitor of β-glucuronidase, an enzyme that produces toxic and carcinogenic compounds in the gut lumen through glucuronide hydrolysis, and has been associated with colorectal cancer pathogenesis163–166 (Fig. 1). Kombucha also contains the SCFA acetic acid that, in conjunction with large proteins and catechins, contributes to the antimicrobial activity of kombucha167,168. Acetic acid is also a major bioactive component in vinegar, which can improve glycaemic control through several mechanisms including activation of the free fatty acid receptor 2 (FFAR2) receptors localized in the enteroendocrine L cells of the intestinal lumen, which in turn leads to increased glucagon-like peptide 1 (GLP1) secretion169.

Compounds with prebiotic potential

Prebiotics are defined as “a substrate that is selectively utilized by host microorganisms conferring a health benefit”170 (Box 1). Certain FFs have been reported to contain compounds that have prebiotic potential as a part of their food matrix171. These FFs include fermented beverages such as wine and beer and fermented cereals and vegetables, which can contain oligosaccharides, β-glucans and polyphenols, all of which have demonstrated prebiotic potential172–175. Additionally, in certain cases, compounds with prebiotic potential might be produced by microorganisms during the fermentation process. For example, exopolysaccharides synthesized by LAB might act as prebiotic substrates for the gut microbiota176 (as detailed below in ‘Exopolysaccharides’). Despite this finding, research relating to the abundance and diversity of prebiotics in FFs remains limited171. Nevertheless, these compounds remain subjects of interest as prebiotics and might positively modulate gastrointestinal health through various mechanisms139, with one of the primary mechanisms involving the production of SCFAs such as acetate, butyrate and propionate139.

Exopolysaccharides

A wide range of FF-associated microorganisms can produce exopolysaccharides, which are long sugar polymers consisting of repeating units of monosaccharides or oligosaccharides that have gained a lot of attention due to their potential health benefits177. Exopolysaccharides can be classified into heteropolysaccharides, which are polymers of different monosaccharides, and homopolysaccharides, which are polymers of a single sugar moiety178. Homopolysaccharide synthesis occurs external to the cell, where membrane enzymes assemble sugars into exopolysaccharide chains with homopolysaccharides generally associated with prebiotic properties179,180. By contrast, heteropolysaccharides are associated with the modulation of antioxidant effects or host immune function, among others179,180. The compositional and structural characteristics of exopolysaccharides produced are dependent on both strain and species176,181–183 and, unsurprisingly, these characteristics are important determinants of their effects on host health (reviewed179). Exopolysaccharides are usually resistant to digestion in the upper gastrointestinal tract leading to their fermentation by gut microorganisms to produce SCFAs; that is, they show prebiotic effects176,184,185 (Fig. 1). Additionally, various experiments, primarily in vitro and in animal models, have shown that exopolysaccharides can modulate cytokine production by immune cells186, inhibit pathogens or pathogen adhesion to the intestinal epithelium187–189, suppress inflammation190, promote intestinal barrier integrity187,191, act as antioxidants186 and facilitate weight management192,193, and might inhibit the proliferation of colon and gastric cancer cells194–196. For example, the exopolysaccharide kefiran, produced by Lactobacillus kefiranofaciens from kefir grains197,198, has been shown in murine models to promote increased IgA production in B cells in both the small and large intestine, impart potential benefits in relation to constipation and weight maintenance, and modulate inflammation through influencing cytokine production189,192,199,200.

Phenolic compounds

Phenolic compounds are a structurally and functionally diverse group of secondary plant metabolites that can be classified into flavonoids, phenolic acids and tannins based on their structure201 (reviewed elsewhere202). These compounds can be transformed in various ways by fermentative microorganisms201 as well as the intestinal microbiota203 in a strain-dependent and species-dependent manner to influence health. In general, fermentation of vegetables, cereals and other plant-based matrices releases bound phenolics from the food matrix and catalyses the biotransformation of complex phenolics to simpler compounds, both of which lead to increased bioavailability and bioaccessibility of such compounds204,205. Some of these metabolites, such as alkyl catechols, can activate the master regulator of oxidative stress response in mammals, NRF2, and induce the expression‎ of anti-oxidant and detoxifying enzymes that provide protection against free radical and chemical damage206. An excellent example of fermentative increase in phenolic concentration are fermented tea-based beverages, including the aforementioned kombucha207. Although catechins are the principal polyphenols in green tea-based kombucha208, theaflavins and thearubigins are the main polyphenols in black tea-based kombucha209. With a greater diversity and abundance of phenolic compounds, the latter has a better antioxidant capacity, whereas green tea kombucha has shown both antibacterial activity and antiproliferative properties against colorectal adenocarcinoma cell lines in vitro207. Notably, polyphenols have been reported to generally stimulate the growth of beneficial gut microorganisms and inhibit pathogenic bacteria in vitro and in vivo (in humans and in animal models)210–215 (Fig. 1).

The flavonoid kaempferol is formed during fermentative breakdown of glucosinolate in plant-based food matrices, and has been shown to possess antioxidant activity and to attenuate cytokine-induced reactive oxygen species in vitro in hepatocellular carcinoma cells (HepG2-C8) through the NRF2 pathway216,217. Alternatively, ferulic acid is a phenolic acid with potent antioxidant properties found in rice and wheat bran that is substantially enriched upon fermentation218,219. Isoflavones (such as genistein, daidzein, quercetin and glycitein), a type of flavonoid polyphenol, are naturally occurring phytoestrogens that are frequently encountered in soybeans220,221. Isoflavone glycosides are hydrolysed into their corresponding aglycones during fermentation of soybean-based FFs such as sufu, douchi, miso, natto, chungkokjang, doenjang, tempeh and thua nao, leading to an increase in their concentration222–225. Importantly, these soy aglycones are more quickly absorbed in the human digestive tract than their glycoside counterparts, leading to increased plasma concentrations and, potentially, in turn exhibit better effectivity226. Importantly, similar benefits can be contributed by the gut microbiota as well, which can transform polyphenol glycosides and aglycones into various derivatives through a diverse array of different reactions227 (Fig. 1). Soy isoflavones have also been shown to positively influence gastrointestinal motility, contractility and secretory functions, and intestinal permeability in vitro and in animal models (reviewed elsewhere221). Genistein might also exert antiproliferative effects, as observed in vitro, through promotion of apoptosis, induction of cell cycle arrest, and inhibiting cancer cell migration, among others228–230. Although fermentation increases the total bioavailable phenolic content in FFs, which is considered beneficial for health, it also releases tannins from the food matrix that could chelate minerals such as calcium, phosphorus and iron, thereby decreasing mineral bioavailability. This effect is somewhat counteracted by fermentation-associated degradation of other mineral chelators such as oxalates and phytates136.

Fermentative removal of undesirable compounds

Food fermentation can remove some undesirable compounds from foods, and thereby improve food quality and safety, and avoid potentially negative effects on human health231. This section provides examples of removal of undesirable compounds through fermentation and its effects on gastrointestinal health and disease.

Mycotoxins

Mycotoxins are a diverse group of secondary metabolites commonly produced by filamentous toxigenic fungi with adverse effects on human health, such as acute mycotoxicosis and death, and chronic effects, such as their ability to induce growth and developmental defects and immunosuppression, and their mutagenicity and carcinogenicity232. Mycotoxins can be found in crops and foods. Best practices in farming, food storage and food processing aim to reduce mycotoxin levels in food products. During the process of food fermentation, levels of mycotoxins (such as patulin and aflatoxin) can be reduced or they can even be completely removed, leading to a safer product233. Patulin, produced by Byssochlamys spp., Penicillium spp. and Aspergillus spp., is commonly found in contaminated fruits and, on the basis of in vitro and animal studies, can cause intestinal barrier damage, and has been linked to endotoxaemia, inflammation and intestinal lesions, as well as damage to other organs234,235. Cider production by Saccharomyces cerevisiae results in the conversion of patulin into the less toxic ascladiol236. Aflatoxins, of which more than 18 known forms are produced by different Aspergillus and Emericella spp.237–239, are found in foods such as grains and nuts (aflatoxin B1), and dairy products (aflatoxin M1)240. Aflatoxins have been associated with different types of cancer, and liver cancer in particular, whereas chronic exposure can also cause various other severe diseases and states as a result of their teratogenic, cytotoxic and immunosuppressive effects241. In children, aflatoxin exposure has been associated with stunting and underweight242. The utility of fermentation of aflatoxins was shown in vitro by the absorbance and degradation of aflatoxin M1 in milk following fermentation with LAB and yeast strains243, absorbance of various mycotoxins by microorganisms from milk kefir244, and the fermentation of bread with LAB, which can inhibit the growth of Aspergillus parasiticus and reduce aflatoxin production245. Fumonisins, produced by Fusarium verticillioides, have been linked to oesophageal cancer and have been suggested to impair intestinal barrier function232,246. LAB-based fermentation of maize meal and porridge resulted in a reduction of fumonisin B1 by 74.6% and 30%, respectively247,248. Detoxification through fermentation can be an alternative to other treatments240, but requires thorough case by case eval‎uation. An increase in mycotoxin levels during food fermentation is considerably less common and is typically associated with an unsuccessful fermentation233.

Lactose

In individuals with lactose intolerance, undigested lactose will induce osmosis in the lumen, and can also be fermented by components of the gut microbiota in a manner that induces gastrointestinal symptoms, such as diarrhoea and discomfort249. Yogurt, a fermented dairy product, has a strong buffering capacity (three times as much acid is required to change its pH from 4.1 to 2.0 than is required to acidify milk), and this aspect is thought to play a key part in the passage of intact lactase, and indeed microbial cells, through the stomach250. In vitro studies have shown that the activity of lactase originating from yogurt increases in the presence of bile acids, which is thought to permeabilize yogurt culture cells, thereby allowing more lactose to enter the bacterial cells and be degraded251,252. This step, along with a slower gastrointestinal transit time, leads to >90% of the lactose in yogurt being digested in the small intestine into glucose and galactose in lactase-deficient individuals250,253–255. The benefits of yoghurt consumption are borne out by human studies. In early investigations by Kolars et al., following administration of 18 g of lactose in water, milk or yogurt to individuals with lactase deficiency, those receiving yogurt reported only one-third of hydrogen excretion/breath hydrogen, an indicator of lactose malabsorption, compared with those receiving lactose in water or milk254. Additionally, yogurt led to markedly lower incidence of diarrhoea and flatulence than milk, with 80% of participants ingesting milk reporting such symptoms compared to 20% of yogurt-ingesting participants254. These observations were supported by several subsequent studies253,254,256, to the extent that the evidence was considered sufficient by the European Food Safety Authority (EFSA) to authorize a health claim for alleviation of symptoms for lactose maldigestion by yogurt cultures (that is, Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus) 257. Notably, this benefit might also be applicable to other fermented dairy foods. Indeed, milk kefir is also well tolerated by people with lactose malabsorption258; it led to a significant lowering of breath hydrogen (224 ± 39 ppm for milk; 87 ± 37 ppm for plain milk kefir; P < 0.001) and perceived severity of flatulence compared with milk258. Hard and/or aged cheeses, which have undergone long fermentations, often have very low to undetectable lactose concentrations (for example, cheddar 0.09–0.5 g/100 ml), whereas soft or young cheeses, which undergo shorter fermentations, usually contain higher amounts of lactose (cottage cheese 1.0–3.1 g/100 ml) (reviewed in ref. 259).

FODMAPs

Irritable bowel syndrome (IBS) is a disorder of gut–brain interaction that affects 6% of the global population260. A low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet has been shown to improve gastrointestinal symptoms and quality of life scores in people with IBS in several systematic reviews and meta-analyses261,262. Notably, many FFs, such as tempeh and soy sauce, are naturally low in FODMAPs, even in instances where the raw ingredients are high in FODMAPs41. In addition, α-galacto-oligosaccharides, a type of FODMAPs commonly found in legumes, such as soybeans, are found in low concentrations in fermented soybean products, such as tofu, tempeh and soy sauce263. Similarly, leavening of dough with S. cerevisiae can reduce fructan content by 40–80% compared with the unfermented flour41. Even greater reductions can be achieved when more complex microbial communities are used, as is the case for sourdough manufacture, or by choosing strains for inoculating the fermentation (starter cultures) that are highly efficient in reducing FODMAP levels264–266. Thus, it is likely that FFs produced under specific fermentation conditions (such as specific microorganisms, fermentation time) might be better tolerated by people who report worsened gastrointestinal symptoms following high FODMAP consumption266.

Gluten

Coeliac disease is an autoimmune condition, whereby the consumption of gluten, found in different cereals, leads to an immune reaction (autoantibody production), leading to symptoms including chronic diarrhoea, chronic fatigue, weight loss, iron deficiency, osteoporosis, headaches, abdominal pain, bloating and constipation267. Gluten is the name given to a family of alcohol-soluble proteins that contain non-digestible peptides responsible for this immune reaction268. Coeliac disease is estimated to affect up to 1.4% of the world population, and preval‎ence has been increasing268–271. Treatment is a restrictive, lifelong gluten-free diet. Although sourdough fermentation of wheat flours usually does not decrease gluten levels sufficiently to meet the common standards for ‘gluten-free’ products of <20 mg/kg or <20 ppm gluten (Codex Alimentarius, European Commission, and the FDA)272, specifically designed fermentations could potentially be used to create products safe for people with coeliac disease. Indeed, it has been shown that fermentation of wheat flour under optimized conditions, with selected microbial strains and proteases, can be used to prepare baked goods, which can be consumed by patients with coeliac disease without adverse effects273–276. However, despite the promising effects of fermentation in reducing gluten content in grain products, based on current evidence, fermented grain products made from gluten-containing substrates remain unsafe for consumption in the context of coeliac disease.

Trypsin inhibitors

Trypsin inhibitors are a class of heat-labile defence compounds commonly found in plants and especially in legumes, such as soybeans. Trypsin inhibitors inhibit trypsin and chymotrypsin proteases, and therefore interfere with protein digestion, potentially causing hypertrophy or hyperplasia of the pancreas277. Fermentation can be very efficient in removing trypsin inhibitors (for example, >99% reduction in trypsin inhibitors in fermented soybeans278), and in some instances is more desirable than removal by standard cooking approaches because of lower energy costs and retention of nutrients and because the fermented product has a more desirable organoleptic profile, and therefore is more appetizing for consumers279.

Phytic acid

Phytic acid (also referred to as inositol hexakisphosphate or IP6) is the main compound for the storage of phosphorus in seeds. Phytate, the ionized form of phytic acid, chelates divalent metal cations and renders them unavailable for absorption in humans280, contributing greatly to Fe2+ and Zn2+ deficiency in high-phytate diets281. Cooking, soaking, germination and malting, milling and processing, as well as fermentation, can degrade phytic acid and increase the availability of minerals281. Making bread with sourdough starters can reduce amount of phytate by up to 97% from the initial phytate content282, whilst fermentation of Vigna mungo (black-gram dhal) reduced the amount of phytic acid by almost half the initial content283. In cereals, phytases are present in sufficient quantities and their activity is increased during the fermentation due to the lowered pH, allowing efficient degradation of phytic acid (reviewed in ref. 231). In legume fermentations microbial enzymes aid phytate degradation231. Although high-phytate diets can lead to mineral deficiencies, phytate might be beneficial in the prevention of other human diseases, such as diabetes and diseases associated with high serum uric acid280,284,285.

Vicine and convicine

Vicine and convicine are pyrimidine glucosides in faba beans (Vicia faba L.), which can cause favism (an acute haemolytic syndrome) in people with glucose-6-phosphate dehydrogenase deficiency. Favism is likely to be the most frequent form of acute haemolytic anaemia286. Flow soaking or cooking can efficiently detoxify faba beans by reducing the vicine and convicine contents, but have a high demand for water and energy, whereas roasting reduces their concentrations to a lesser extent287. Fermentation of faba bean flour has been shown to be highly efficient for vicine and convicine detoxification: levels of vicine and convicine are undetectable after 48 h of fermentation with L. plantarum DPPMAB24W288.

Cyanogenic glycosides

Cyanogenic glycosides are a group of defence compounds naturally present in a variety of plants, such as bitter cassava, lima beans and linseeds289. Toxicity arises from β-glucosidase enzymatic degradation of cyanogenic glycosides into hydrogen cyanide290. Consumption of cyanogenic glycosides from insufficiently processed bitter cassava, combined with a low-protein diet, can cause a neurological disease called konzo (reviewed elsewhere291). Different processing techniques are available to reduce the cyanogenic glycoside content, such as grating, sun drying and cooking292. Fermentation of cassava reduces cyanogenic glycosides, increases nutritional value, and makes cassava safe for human and animal consumption293,294.

Fermentation-associated microorganisms

Although some FFs have a pasteurization or filtration step before consumption, others are eaten when the live microorganisms are still present. Besides the products of their metabolism, these live microorganisms can be regarded as potentially conferring effects on gut health themselves. The live microorganisms in these foods can be diverse, encompassing bacteria, yeast and other fungi, depending on the food. However, they are generally not characterized to the strain level and therefore do not fulfil the criteria for probiotics295. It is important to make the distinction between FF-associated microorganisms and probiotics. Briefly, probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” and which need to be “isolated, characterized and a credible case presented for their health effects”295 (Box 1). FFs such as yoghurt might be produced with probiotic starter strains for which health benefits have been shown previously and can therefore be referred to as probiotics. Despite the distinction between FF microorganisms and probiotics, the close taxonomic relationship between some representatives of both16,17, especially among some species of LAB, suggest that FFs can be an important reservoir for potential probiotics. The distinction between FF microorganisms and probiotics has been discussed in detail previously5,296.

Old friends’ hypothesis

The ‘old friends’ hypothesis suggests that a lack of exposure to microorganisms in the industrialized world is associated with the increase in allergic and autoimmune diseases that has been observed over the past few decades297. This lack of exposure has been attributed to a variety of factors, including changes to food production systems that decrease the levels of microorganisms in foods298 and a shift from fermented to more heavily processed foods299–302. The proponents of the hypothesis propose that humankind has co-evolved with microorganisms, particularly beneficial ones or ‘old friends’, and that microbial exposure is necessary to train our immune system to respond appropriately to external challenges303.

Microbial exposure

The consumption of FFs has been suggested as a safe way to increase microbial exposure, particularly in Western countries5,302. FFs can be rich in microorganisms, such as LABs, AABs and yeasts, and commonly contain up to 109 colony-forming units (CFU) per millilitre or per gram if the microorganisms are not removed or inactivated (such as through filtration or pasteurization)9,304. Table 1 shows estimated levels of live microorganisms per gram of FF; it should be noted that the amount of live microorganisms varies greatly between different fermentation practices, sampling time points and preservation techniques9 . Lang et al. compared three different meal plans: the average American diet, a vegan diet and a US Department of Agriculture (USDA)- recommended meal plan. The average American diet and vegan diet contained a microbial load of 1.4 × 106  CFU and 6 × 106  CFU per day, respectively. The USDA-recommended meal plan contained 200–900 times higher microbial loads (1.3 × 109  CFU per day) than the other meal plans, which was attributed to the presence of FFs with live cultures, which were missing in the other meal plans305. The number of different species in FFs ranges from those in which a small number of species are used in starter cultures (for example, yoghurts) to those with complex communities as is the case in artisanal kefir and in many spontaneous FFs16,306,307.

FFs produced via spontaneous fermentation frequently contain higher numbers of different species as well as higher diversity than foods produced from starter cultures16. It is desirable to preserve microbial communities of artisanal and traditional FFs to retain the unique organoleptic profiles and potential benefits for human health308. Taken together, these observations suggest that FFs with live microorganisms are an accessible vehicle to supplement the gut with live microorganisms in diets that are otherwise low in microbial load. Consistent with the old friends hypothesis, FF microorganisms have been shown to aid host health via interactions with the host immune system and positive modulation of the gut microbiota in humans. A study published in 2021 investigated the consequences of consumption of a FF-enriched diet in healthy adults (n = 18 per diet) and found a decrease in inflammatory markers and an increase in gut microbiota diversity20. In another epidemiological study including 46,091 American adults, increased consumption of dietary microorganisms from a range of foods, including FFs, was linked to modest positive health outcomes including improved markers for cardiovascular health and inflammation, and reduced BMI, plasma glucose levels and insulin levels309,310. This finding is consistent with cohort studies that have, for example, shown a reduced risk of atopic dermatitis and food allergies with increased cheese consumption311–313. The research on FFs and their effect on inflammatory bowel disease is limited, but one randomized controlled trial (RCT) investigating milk kefir showed improvements in clinical markers in patients (treatment (n = 25), control (n = 20)) with ulcerative colitis or Crohn’s disease314.

Fermented foods and the gut microbiota

A phylogenetic comparison of FF and gut (faecal) metagenome assembled genomes (MAGs) showed that, for some LAB, these MAGs are very closely related, suggesting a FF-based origin for some gut LAB17. This finding is complemented by direct evidence that some FF microorganisms can survive gut transit and can be cultured from faeces315–318. Such survival and/or transit is affected by factors such as the food matrix (for example, with respect to buffering capacity), strain genetics and host factors319–322. Although it is likely that most FF microorganisms do not have the capacity to colonize the human gut, there might be some exceptions that are able to colonize for a limited number of days or weeks (discussed elsewhere323,324). FF-associated microorganisms, if they are metabolically active in the gut, are likely to be involved in crossfeeding and competition for nutrients with resident microorganisms325 (Fig. 1). Indeed, studies with the model organisms Drosophila melanogaster326 and Zootermopsis angusticollis327 have shown that FF-associated microorganisms (L. plantarum and Lactococcus lactis, respectively) can be involved in crossfeeding with host microbes. Studies are required to determine whether similar crossfeeding between FF microorganisms and resident microorganisms also occurs in the human gut.

Immune modulation

Investigations have taken place to determine the molecular mechanisms by which FFs might help regulate immune function. It is likely that some of these mechanisms are similar to those studied in much greater depth among probiotics and postbiotics, such as surface molecules in probiotic bacteria, referred to as microorganism-associated molecular patterns, which are recognized by corresponding host pattern recognition receptors (such as Toll-like receptors) leading to host– microorganism crosstalk and immune system modulation328. Some of the key mechanisms of immune system modulation by microorganisms have been investigated for FF microorganisms in experimental models as well: protection of intestinal barrier, prevention of penetration of pathogens into epithelial cells and prevention of bacterial translocation329,330; increase in anti-inflammatory cytokine levels and reduction in pro-inflammatory cytokine levels331,332; limiting pathogenic growth via antimicrobial compounds333; regulation of T helper 1 (TH1) and TH2 cell function334; and regulation of TLR expression‎335–337.

Fermented foods and the small intestine

Importantly, most gut microbiome studies rely on the analysis of faecal samples, which is somewhat reflective of the colonic microbiome. Although the colon is diverse and abundant in resident microorganisms (1010–1011 cells per millilitre or gram)323,338, the small intestine is less densely populated (106 –108 cells per millilitre or gram) and less diverse (being dominated by Veillonella, streptococci, lactobacilli and clostridia)323,339. Thus, although the small intestine has not been the subject of extensive research to date, it might indeed be an environment where FF microorganisms could have a more substantial influence, as FF microorganisms will be present in a higher relative abundance than the resident microorganisms323. In a 2023 study, 16 patients with an ileostomy were given fermented milk products at breakfast. The fermented milks contained either Lacticaseibacillus rhamnosus or S. thermophilus and L. delbrueckii subsp. bulgaricus. Metataxonomic profiling of ileal samples, collected after breakfast, showed that the small intestinal microbiome contained transiently up to 50% product-derived FF microorganisms. Between different sampling days during the intervention a high variability in the abundance of product-derived FF microorganisms was observed. The fermented milk led to individual-specific changes in the small intestinal microbiome composition, whilst not affecting the levels of SCFAs in ileostomy output and gastrointestinal permeability340.

Limitations

Effects of FF consumption on host microbiota composition are frequently assessed through changes in relative abundance, and/or CFU counts, and/or diversity measures. Notably, change to the gut microbiota composition is not necessarily a predictor or biomarker of health, although it might be more important in individuals with a suboptimal gut microbiota336. In other instances, changes to the metabolome or metatranscriptome have been evident in the absence of substantial changes in gut microbiota composition20,341–343. Ultimately, it might be that changes in the metabolome, metatranscriptome or metaproteome of gut microorganisms and/or the host will provide greater insights into the health benefits of FFs, but more high-quality multi-omics studies are required to address this issue.

Heat-inactivated and cell-free fermented foods

As noted, several components within FFs can contribute to health and, therefore, the presence of live microorganisms is not always necessary to confer health benefits. It is worth comparing these FFs without living microorganisms to postbiotics. Postbiotics are defined as “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”344 (Box 1). FFs without living microorganisms might be able to fulfil the requirements for postbiotics, if inactivated cells or cell components remain in the food and a health benefit is sufficiently shown. If the FF does not contain any inanimate cells or cell components, then it cannot fulfil the definition for a postbiotic. For example, one study in humans with pasteurized and unpasteurized sauerkraut showed that both substantially decreased gut symptoms in people with IBS (n = 34)345, where a case could be made for the pasteurized sauerkraut as a postbiotic, if the case for its health benefits is sufficiently strong. Further insights have been provided through studies with milk kefirs. More specifically, milk kefirs have been shown to lower plasma cholesterol and liver triacylglycerol in mice fed a high-fat diet, but these effects are dependent on the microbial composition of the kefir. Briefly, different microbial milk kefir species were combined to create a ‘pitched’ kefir. The pitched kefir contained nine milk kefir microorganisms that, in combination, retained these benefits. Importantly with respect to this discussion, a cell-free pitched kefir, and a heat-inactivated pitched kefir also reduced weight gain in male mice, but not in female mice, on a high-fat diet346,347. All kefir-containing diets were able to reduce plasma cholesterol levels, whereas only the pitched kefir with live microorganisms was able to reduce liver cholesterol levels in male and female mice348. These investigations have now been translated to humans, and it was demonstrated that consumption of the pitched milk kefir resulted in a reduction in LDL cholesterol levels that did not occur when a commercial milk kefir control (produced with strains not representative of artisanal milk kefir) was used349, again highlighting the importance of the microbial composition of FFs with respect to health benefits. Another way to harness the health benefits of FFs is via so-called fermentates, which are fermentation products that undergo a drying process after the fermentation (typically freeze-drying or spray-drying) to extend the shelf-life of these powdered products whilst, ideally, maintaining the beneficial properties of the fermented product350, even in situations in which the FF microorganisms have been inactivated. The health benefits of fermentates are frequently attributed to the bioactive metabolites produced during the fermentation350. Ultimately, whilst producing FFs that do not contain live microorganisms is convenient from the perspective of facilitating a longer shelf-life or storage at an ambient temperature, there is a need to ascertain on a case by case basis if the health benefits are retained.

Future outlook

Growing global consumer interest in FFs, especially among Western populations, is largely driven by their perceived benefits beyond basic nutrition11,351. However, except for yogurt and some other well-known FFs including kimchi, sauerkraut and kefir, few FFs have been the focus of human clinical studies5,11,303,352 (reviewed in detail in refs. 11,22,353–355). Indeed, evidence for health benefits of FFs is often limited to chemical analyses, in vitro assays or animal models11. A better understanding of the health benefits of FFs, including in gastrointestinal health, will necessitate gathering information from population-based diet and health databases (such as the NHANES) as well as new RCTs303,309. However, population-based databases often gather information through food frequency questionnaires and other approaches that usually lack granularity vis-à-vis FFs (critical aspects such as microbial strain composition and quantity, viability and fermentation times, among other nutritional information, are not reported). Methods employed for information collection in such surveys will therefore need to be modified and updated accordingly. New RCTs should be designed to account for health outcomes with respect to different FFs (such as kefir or kimchi),

FF categories (such as cereal-based or dairy-based FFs), food groups (such as fermented vegetables, meats, dairy, and so on), whole diets with varying contents of FFs (such as whole diets high versus low in FFs), viability status of FF-associated microorganisms, and pitched FFs with defined strains and nutrient composition. Anticipated challenges for such RCTs include limitations in blinding, adequate placebo controls, cohort and/or population size, dietary recall and intervention durations, among others5 . Some of the key considerations for undertaking high-quality RCTs of FFs are discussed in Box 2. Importantly, results from observational studies and RCTs need to be supplemented with studies directed towards gaining an understanding of the modes of action for different FFs. Such studies could involve investigations of specific components of the FFs, strain tracking from FFs through the gut, broader ‘fermentome’ surveys, and gene expression‎ analyses of both FF-relevant host tissue and/or systems among others, with possible challenges including analyses of gut samples other than faeces. Taken together, evidence from such studies will enable a foundational understanding of the health-promoting activities of FFs and how they vary with food type, microbial strains, fermentation methods and post-production handling. Notably, such studies are also crucial to the development of pitched or designer FFs, which can incorporate known microbial strains and defined nutritional features that might be directed towards reproducible support in various ailments. Ultimately, this evidence is critical for providing justification to incorporate FFs as a recommended food category in global food guidelines, in which these foods are noticeably frequently absent, arguably due to a current lack of evidence of their health benefits356. The presence of potentially beneficial, live FF-associated microorganisms, some of which have been studied in great detail compared with their associated FFs, has also added to the advocacy for FFs to be included in dietary recommendations22,303,356,357. A simultaneous increment in the number of available food standards for FFs, which are currently sparse296, is also needed along with the appropriate revision and harmonization of global regulatory guidelines for FFs, which remain primarily concerned with food safety5,296. FF manufacturers, particularly those of innovative functional FFs, would benefit from clear definitions and criteria (for example, manufacturing, quality and geographical requirements) for FFs. Over the past decade, the application of high-throughput methodologies has enabled the identification of the core microbial and chemical components of certain FFs, leading to the addition of global and regional standards for FFs such as kimchi, tempe and doogh, among others296. It is expected that more such standards will be created as we improve our understanding of FFs, with the creation of such food standards providing the building blocks for future harmonized global regulations for FFs.

Conclusions

The benefits of FFs with respect to gut and, indeed, systemic health is becoming increasingly evident with a growing corpus of evidence from a diverse array of studies. As discussed in this Review, the unique nature of FFs as foodstuffs can result in there being a number of different health benefits accorded by the fermentative process beyond those offered by the native food matrix. Novel compounds produced during fermentation, such as bioactive peptides and exopolysaccharides, among others, as well as FF-associated microorganisms with potentially health-promoting characteristics remain of particular interest. Notably, whilst the mechanisms responsible for such benefits are well understood for some FFs, much remains unknown. Moving forward, interdisciplinary studies employing various omics-based methods and culminating in RCTs specifically designed to investigate FFs will be necessary to fully capitalize on the therapeutic and clinical potential of FFs.

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