Re: 음식 --＞ 장내미생물 변화... 인체 건강 2017년 리뷰

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• Open access
• Published: 08 April 2017

Influence of diet on the gut microbiome and implications for human health

• Rasnik K. Singh, 
• Hsin-Wen Chang, 
• Di Yan, 
• Kristina M. Lee, 
• Derya Ucmak, 
• Kirsten Wong, 
• Michael Abrouk, 
• Benjamin Farahnik, 
• Mio Nakamura, 
• Tian Hao Zhu, 
• Tina Bhutani & 
• Wilson Liao 

Journal of Translational Medicine volume 15, Article number: 73 (2017) Cite this article

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Abstract

Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically eval‎uates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient.

초록

최근 연구들은 장내 미생물군이

염증성 장 질환, 비만, 제2형 당뇨병, 심혈관 질환, 암 등

여러 만성 질환의 위험을 조절하는 데 중요한 역할을 한다는 것을 제시했습니다.

동시에,

식단이 미생물군을 형성하는 데 중요한 역할을 한다는 것이 밝혀졌으며,

실험 결과 식이 변화가 24시간 이내에 큰 일시적인 미생물 변화를 유발할 수 있음을 보여주었습니다.

이 연관성을 고려할 때,

식이를 통해 미생물 구성을 변경하는 것이 치료적 유용성을 가질 수 있습니다.

이 리뷰는

일반적인 식이 성분이 장내 미생물군집에 미치는 영향을 평가하기 위해

현재까지의 데이터를 체계적으로 검토합니다.

특정 유형의 식품 섭취가

기존 호스트 세균 속의 예측 가능한 변화를 유발한다는 것을 보여줍니다.

또한 이러한 세균의 정체성이 호스트의 면역 및 대사 매개변수에 영향을 미치며,

이는 인간 건강에 광범위한 영향을 미칠 수 있습니다.

이러한 연관성을 이해하는 것은 의료진과 환자 모두에게 큰 도움이 될 것입니다.

Background

The gut microbiome

The human gut microbiome encompasses 1014 resident microorganisms, including bacteria, viruses, fungi, and protozoa, that are commensal with the human intestinal tract [1]. Among these, bacteria represent the most well studied group and will be the main focus of this review. Overall the predominant bacterial groups in the microbiome are gram positive Firmicutes and gram negative Bacteroidetes [2, 3]. Recently, it has been shown that microbiota can effectively be subdivided into different enterotypes, each enriched by particular bacterial genera, but that all seem to share high functional uniformity [4]. This uniformity exists regardless of several host properties, such as age, sex, body mass index, and nationality [5].

The majority of microorganisms reside within the more distal parts of the digestive tract, where their biomass surpasses 1011 cells per gram content [6]. Microbes in the distal gut contribute to host health through biosynthesis of vitamins and essential amino acids, as well as generation of important metabolic byproducts from dietary components left undigested by the small intestine [7]. Short chain fatty acid (SCFA) byproducts such as butyrate, propionate, and acetate act as a major energy source for intestinal epithelial cells and may therefore strengthen the mucosal barrier [8]. Additionally, studies conducted using germ-free mice suggest that the microbiota directly promote local intestinal immunity through their effects on toll-like receptor (TLR) expression‎ [9], antigen presenting cells, differentiated T cells, and lymphoid follicles [10, 11], as well as by affecting systemic immunity through increased splenic CD4+ T cells and systemic antibody expression‎ [12].

These recorded benefits and more have led to growing interest in the ability to modify the gut microbiota. An acute change in diet—for instance to one that is strictly animal-based or plant-based—alters microbial composition within just 24 h of initiation, with reversion to baseline within 48 h of diet discontinuation [13]. Furthermore, the gut microbiome of animals fed a high-fat or high-sugar diet is more prone to circadian rhythm disruption [14]. Studies also suggest that overwhelming systemic stress and inflammation—such as that induced via severe burn injury—can also produce characteristic acute changes in the gut microbiota within just one day of the sustained insult [15].

장 미생물군집

인간 장 미생물군집은 인간 장내와 공생하는

세균, 바이러스, 곰팡이, 원생동물 등 10¹⁴개의 미생물로 구성됩니다 [1].

이 중 세균은 가장 잘 연구된 그룹으로,

본 리뷰의 주요 초점이 될 것입니다.

미생물군집에서 주요 세균 그룹은

그람 양성 Firmicutes와 그람 음성 Bacteroidetes입니다 [2, 3].

최근 연구에서 미생물군은 특정 세균 속으로 풍부하게 구성된

서로 다른 장형으로 효과적으로 분류될 수 있지만,

모든 장형은 높은 기능적 일관성을 공유한다는 것이 밝혀졌습니다 [4].

이 일관성은

연령, 성별, 체질량 지수, 국적 등 호스트의 여러 특성에도 불구하고 존재합니다 [5].

대부분의 미생물은 소화관의 더 먼 부분에 거주하며,

그 생물량은 1그램당 10¹¹ 세포를 초과합니다 [6].

소화관의 먼 부분에 있는 미생물은

비타민과 필수 아미노산의 생합성, 소장에서 소화되지 않은 식이 성분으로부터

중요한 대사 부산물을 생성함으로써

호스트 건강에 기여합니다 [7].

단쇄 지방산(SCFA) 대사산물인

부티레이트, 프로피오네이트, 아세테이트는

장 상피 세포의 주요 에너지원으로 작용하며,

따라서 점막 장벽을 강화할 수 있습니다 [8].

또한 무균 마우스를 대상으로 한 연구는

미생물이 톨 유사 수용체(TLR) 발현[9],

항원 제시 세포, 분화된 T 세포, 림프구 소체[10, 11]에 영향을 미쳐

국소 장 면역력을 직접 촉진하며,

비장 내 CD4+ T 세포 증가와 전신 항체 발현을 통해

전신 면역력에도 영향을 미친다는 것을 보여주었습니다[12].

이러한 기록된 혜택과 더 많은 연구 결과는

장 미생물군집을 조절하는 능력에 대한 관심을 높이고 있습니다.

식이 요법의 급격한 변화—예를 들어 동물성 또는 식물성 식이로의 전환—는

식이 시작 후 24시간 이내에 미생물 구성 변화를 유발하며,

식이 중단 후 48시간 이내에 기본 수준으로 회복됩니다 [13].

또한 고지방 또는 고당분 식이를 섭취한 동물의 장 미생물군은

생체 리듬 장애에 더 취약합니다 [14].

연구 결과, 심각한 화상 손상과 같은 과도한 전신 스트레스와 염증은

지속적 손상 후 단 하루 만에 장 미생물군에 특이적인

급성 변화를 유발할 수 있다는 것도 밝혀졌습니다 [15].

The microbiome in disease

Studies examining the composition and role of the intestinal microbiome in different disease states have uncovered associations with inflammatory bowel diseases (IBD), inflammatory skin diseases such as psoriasis and atopic dermatitis, autoimmune arthritis, type 2 diabetes, obesity, and atherosclerosis. For instance, IBD patients tend to have less bacterial diversity as well as lower numbers of Bacteroides and Firmicutes—which together may contribute to reduced concentrations of microbial-derived butyrate. Butyrate and other SCFAs are thought to have a direct anti-inflammatory effect in the gut [16]. Furthermore, different indices of Crohn’s disease activity have each been characterized by specific gut mucosa-attached bacteria, that in turn are significantly influenced by anti-TNF therapy [17]. The relative abundance of different bacteria may mediate intestinal inflammation and Crohn’s disease activity through effects on local regulatory T cell populations [17, 18]. Furthermore, overrepresentation analysis has shown that enzymes enriched in IBD microbiomes are more frequently involved in membrane transport, which could support a “leaky gut hypothesis” contributing to the disease state [19, 20]. Interestingly, autoimmune Th17 differentiation from naïve T cells appears to be dependent on the segmented filamentous bacteria. Studies have shown that Th17 cells are absent in the small-intestinal lamina propria of germ-free animals, which is the major site of their differentiation. Furthermore, introduction of segmented filamentous bacteria is sufficient to trigger autoimmune arthritis in these animals through promotion of Th17 cell development in the lamina propria and spleen [20, 21]. The gut microbiota of patients with type 2 diabetes has been functionally characterized with diabetes-associated markers, showing enriched membrane transport of sugars and branched-chain amino acids, xenobiotic metabolism, and sulphate reduction along with decreased bacterial chemotaxis, butyrate synthesis and metabolism of cofactors and vitamins [22].

미생물군집과 질병

다양한 질병 상태에서 장 미생물군집의 구성과 역할을 조사한 연구들은

염증성 장 질환(IBD), 건선 및 아토피 피부염과 같은 염증성 피부 질환, 자가면역성 관절염, 제2형 당뇨병, 비만,

동맥경화증과의 연관성을 밝혀냈습니다.

예를 들어,

IBD 환자는 세균 다양성이 낮고 Bacteroides 및 Firmicutes의 수가 적으며,

이 두 그룹은 미생물 유래 부티레이트 농도 감소에 기여할 수 있습니다.

부티레이트와 다른 단쇄 지방산(SCFAs)은

장에서 직접적인 항염증 효과를 가질 것으로 추정됩니다 [16].

또한 크론병 활동의 다양한 지표는

각각 특정 장 점막 부착 세균에 의해 특징지어지며,

이는 항-TNF 치료에 의해 크게 영향을 받습니다 [17].

다양한 세균의 상대적 풍부도는

지역 조절 T 세포 군집에 미치는 영향을 통해 장 염증과 크론병 활동을 매개할 수 있습니다 [17, 18].

또한 과표현 분석은 IBD 미생물군집에 풍부한 효소들이 막 수송에 더 자주 관여한다는 것을 보여주었으며, 이는 질병 상태에 기여하는 “누출 장 가설”을 지지할 수 있습니다 [19, 20]. 흥미롭게도, 자동면역 Th17 세포의 분화(naive T 세포에서)는 분절형 필라멘트 박테리아에 의존적입니다. 연구 결과, 무균 동물(germ-free animals)의 소장 점막 상피층(lamina propria)에서 Th17 세포가 결여되어 있으며, 이는 그들의 분화 주요 부위입니다. 또한, 분절형 필라멘트 세균을 도입하면 이 동물에서 장 점막과 비장에서 Th17 세포 발달을 촉진하여 자가면역 관절염을 유발하는 것으로 나타났습니다 [20, 21]. 2형 당뇨병 환자의 장 미생물군은 당뇨병 관련 표지자를 통해 기능적으로 특성화되었으며, 당과 분지 사슬 아미노산의 막 수송, 외인성 물질 대사, 황산염 환원 증가와 함께 세균의 화학유동성, 부티레이트 합성 및 보조인자 및 비타민 대사 감소가 관찰되었습니다 [22].

Obesity has been characterized by an altered intestinal Bacteroides:Firmicutes ratio, with greater relative abundance of Firmicutes. Furthermore, studies involving microbiota transplantation from obese to lean mice have shown that the obese phenotype is transmissible and may be promoted by microbiota that have increased capacity to harvest energy from the host diet [23]. Risk of atherosclerosis has similarly been linked to the gut microbiota, in particular due to enhanced metabolism of choline and phosphatidylcholine that produces the proatherogenic compound, trimethylamine-N-oxide (TMAO) [24]. A recent study also demonstrated that gut bacteria can produce significant amounts of amyloid and lipopolysaccharides, which are key players in the pathogenesis of Alzheimer’s disease [25]. These observations illustrate the important role of microorganisms in human health and suggest that manipulating them may influence disease activity. While the microbiome of a healthy individual is relatively stable, gut microbial dynamics can certainly be influenced by host lifestyle and dietary choices [26].

In this review, we comprehensively explore the ability of the host diet to modulate gut bacteria, with the hope that this knowledge will guide our understanding of how dietary choices impact human health through alteration of the gastrointestinal ecosystem (Fig. 1, Table 1).

비만은

장내 Bacteroides:Firmicutes 비율의 변화로 특징지어지며,

Firmicutes의 상대적 풍부도가 증가합니다.

또한 비만 마우스에서 마른 마우스로 미생물군집 이식을 진행한 연구에서는 비만 형질이 전파 가능하며, 호스트 식이에서 에너지를 더 효율적으로 추출하는 능력을 가진 미생물군집에 의해 촉진될 수 있음을 보여주었습니다 [23]. 동맥경화증의 위험은 장 미생물과 밀접하게 연관되어 있으며, 특히 콜린과 포스파티딜콜린의 대사 증가로 인해 동맥경화 촉진 물질인 트리메틸아민-N-옥사이드(TMAO)가 생성되기 때문입니다 [24]. 최근 연구에서는 장 세균이 알츠하이머 병의 병리학적 과정에 핵심 역할을 하는 아밀로이드와 리포폴리사카라이드를 상당량 생성할 수 있음을 보여주었습니다 [25]. 이러한 관찰 결과는 미생물이 인간 건강에 미치는 중요한 역할을 강조하며, 이를 조작하는 것이 질병 활동에 영향을 미칠 수 있음을 시사합니다. 건강한 개인의 미생물군은 상대적으로 안정적이지만, 장 미생물 동역학은 호스트의 생활 방식과 식이 선택에 의해 분명히 영향을 받을 수 있습니다 [26].

이 리뷰에서는 호스트의 식단이 장내 세균을 조절하는 능력을 포괄적으로 탐구하며, 이 지식이 식습관이 위장관 생태계의 변화를 통해 인간 건강에 미치는 영향을 이해하는 데 기여할 수 있기를 희망합니다(그림 1, 표 1).

Fig. 1

Impact of diet on the gut microbiome and human health

Full size image

Table 1 Overview of select gut bacterial genera and species commonly affected by diet

Methods

We performed a systematic literature review in September 2015 by searching the electronic MEDLINE database via PubMed. Search terms included combinations of the terms “microbiota”, “intestinal mucosa/microbiology”, “gastrointestinal tract/microbiology”, “gastrointestinal diseases/microbiology”, with “diet”, “food”, “polysaccharides”, “carbohydrates”, “proteins”, “meat”, “fat”, “lactose”, “oligofructose”, “prebiotics”, “probiotics”, “polyphenols”, “starch”, “soy”, “sucrose”, “fructose”, “diet, vegetarian”, “diet, western”, “cereals”, “dietary fiber”, and “dietary supplements”. Articles were reviewed independently by two investigators, R.K.S. and K.M.L, and this was adjudicated by W.L. We limited our search to articles available in English, human studies, and those published between 1970 and 2015. We excluded studies that did not explicitly address the effect of a dietary intervention on microbial composition. Manual searches through reference lists of the articles were also performed to identify additional studies. This resulted in a total of 188 articles being selected for inclusion in this review. Studies describing the relationship between specific dietary components and intestinal microbiota composition ranged from subject number n = 3 to n = 344, with a majority of studies clustered around subject number n = 20 to 70. Study designs were primarily randomized controlled trials, cross-sectional studies, case–control studies, and in vitro studies. In addition to human studies, several animal studies were also included to demonstrate dietary impact on the microbiome under controlled experimental conditions.

Diet and microbiota

우리는 2015년 9월에 PubMed를 통해 전자 MEDLINE 데이터베이스를 검색하여 체계적인 문헌 검토를 수행했습니다. 검색어에는 “미생물군집”, “장 점막/미생물학”, “위장관/미생물학”, “위장관 질환/미생물학”과 “식단”, “식품”, “다당류”, ‘탄수화물’, “단백질”, “고기”, “지방”, “락토스”, “올리고프루토스”, “프리바이오틱스”, “프로바이오틱스”, “폴리페놀”, “전분”, “대두”, “설탕”, “과당”, “식단, 채식”, “식단, 서양식”, “곡물”, “식이 섬유”, “식이 보조제”를 포함했습니다. 논문은 두 명의 연구자 R.K.S.와 K.M.L.에 의해 독립적으로 검토되었으며, 이는 W.L.에 의해 최종 결정되었습니다. 검색은 영어로 작성된 논문, 인간 대상 연구, 1970년부터 2015년 사이에 발표된 논문으로 제한되었습니다. 식이 개입이 미생물 구성에 미치는 영향을 명시적으로 다루지 않은 연구는 제외되었습니다. 논문 참고문헌 목록을 수동으로 검색하여 추가 연구를 식별하는 과정도 진행되었습니다. 이 결과, 본 검토에 포함된 논문은 총 188편으로 선정되었습니다. 특정 식이 성분과 장내 미생물군 구성 간의 관계를 설명한 연구는 대상자 수 n = 3에서 n = 344까지 다양했으며, 대부분의 연구는 대상자 수 n = 20에서 70 사이에서 집중되었습니다. 연구 설계는 주로 무작위 대조 시험, 횡단면 연구, 사례-대조 연구, 체외 연구였습니다. 인간 연구 외에도 통제된 실험 조건 하에서 식이가 미생물군에 미치는 영향을 보여주기 위해 몇 가지 동물 연구도 포함되었습니다.

Protein

The effects of dietary protein on the gut microbiota were first described in 1977. A culture-based study demonstrated lower counts of Bifidobacterium adolescentis and increased counts of Bacteroides and Clostridia in subjects consuming a high beef diet when compared to subjects consuming a meatless diet [27]. With the advances of 16S rRNA sequencing, several studies have been able to comprehensively investigate the impact of dietary protein on gut microbial composition (studies listed in Table 2). Participants were given different forms of protein across these studies, such as heavy animal-based protein from meats, eggs, and cheeses; whey protein; or purely vegetarian sources such as pea protein. A majority of the studies noted that protein consumption positively correlates with overall microbial diversity [13, 28–30]. For example, consumption of whey and pea protein extract has been reported to increase gut-commensal Bifidobacterium and Lactobacillus, while whey additionally decreases the pathogenic Bacteroides fragilis and Clostridium perfringens [31–33]. Pea protein has also been observed to increase intestinal SCFA levels, which are considered anti-inflammatory and important for maintenance of the mucosal barrier [34]. On the contrary, counts of bile-tolerant anaerobes such as Bacteroides, Alistipes, and Bilophila were noted to increase with consumption of animal-based protein (Fig. 2) [13, 29, 30]. This observation can be further supported by an independent study in which the researchers compared the microbiota of Italian children with that of children in a rural African village. Italian children, who ate more animal protein, were enriched for Bacteroides and Alistipes in their microbiota [35]. Notably, one study comparing calorically equivalent high animal protein with high-carbohydrate/fiber plant-based diets reported that subjects’ weights on the plant-based diet remained stable, but decreased significantly by day 3 of the animal protein-based diet (q < 0.05). Although high protein/low carbohydrate intake may promote greater relative weight loss, this dietary pattern may pose a detriment to health. One study found that subjects with a high protein/low carbohydrate diet have reduced Roseburia and Eubacterium rectale in their gut microbiota and a decreased proportion of butyrate in their feces [36]. In their study, De Filippo et al. [35] similarly noted fewer fecal SCFAs in Italian subjects who consumed a protein-rich diet. As an interesting clinical correlate, several studies have demonstrated that IBD patients possess lower fecal counts of Roseburia and other butyrate-producing bacteria than healthy subjects. Healthy subjects, on other other hand, have 10-fold more abundant E. rectale in their intestines [37–39]. These gut bacterial changes may be responsible for the finding in a large participant prospective study (n = 67,581) that high total protein intake, especially animal protein, is associated with a significantly increased risk of IBD [40]. Furthermore, several microbial genera promoted by intake of red meat have also been associated with increased levels of trimethylamine-N-oxide (TMAO), a proatherogenic compound that increases risk of cardiovascular disease [41].

단백질

식이 단백질이 장내 미생물군집에 미치는 영향은 1977년에 처음 보고되었습니다. 배양 기반 연구에서 고기 섭취량이 많은 식단을 섭취한 대상자에서 Bifidobacterium adolescentis의 수가 감소하고 Bacteroides 및 Clostridia의 수가 증가했다는 결과가 고기 섭취가 없는 식단을 섭취한 대상자와 비교하여 확인되었습니다 [27].

16S rRNA 시퀀싱 기술의 발전으로

여러 연구에서 식이 단백질이

장미생물 구성에 미치는 영향을 종합적으로 조사할 수 있게 되었습니다(표 2에 나열된 연구).

이 연구들에서 참가자들은 육류, 계란, 치즈에서 유래한 동물성 단백질, 유청 단백질, 또는 완두 단백질과 같은 순수 채식 소스 등 다양한 형태의 단백질을 섭취했습니다. 대부분의 연구는 단백질 섭취가 전체 미생물 다양성과 긍정적으로 관련되어 있음을 보고했습니다 [13, 28–30]. 예를 들어, 유청과 완두 단백질 추출물 섭취는 장 내 공생균인 Bifidobacterium과 Lactobacillus를 증가시키는 것으로 보고되었으며, 유청은 추가로 병원성 Bacteroides fragilis와 Clostridium perfringens를 감소시켰습니다 [31–33]. 완두 단백질은 또한 장 내 SCFA(단쇄 지방산) 수치를 증가시키는 것으로 관찰되었으며, 이는 항염증 작용을 하고 점막 장벽 유지에 중요합니다 [34]. 반면, 담즙 내성 혐기성 세균인 Bacteroides, Alistipes, Bilophila의 수는 동물성 단백질 섭취와 함께 증가하는 것으로 보고되었습니다(그림 2) [13, 29, 30]. 이 관찰은 이탈리아 어린이와 아프리카 농촌 마을 어린이의 미생물군을 비교한 독립적인 연구로 추가로 뒷받침됩니다. 동물성 단백질을 더 많이 섭취한 이탈리아 어린이의 미생물군에는 Bacteroides와 Alistipes가 풍부했습니다 [35]. 특히, 칼로리가 동일한 고동물성 단백질 식이와 고탄수화물/고섬유질 식물성 식이를 비교한 한 연구에서는 식물성 식이를 섭취한 대상자의 체중이 안정적으로 유지되었지만, 동물성 단백질 식이를 섭취한 대상자의 체중은 3일차에 유의미하게 감소했습니다(q < 0.05). 고단백/저탄수화물 섭취는 상대적 체중 감소를 촉진할 수 있지만, 이 식이 패턴은 건강에 해로울 수 있습니다. 한 연구에서는 고단백/저탄수화물 식단을 섭취한 대상자의 장내 미생물군집에서 Roseburia와 Eubacterium rectale의 감소 및 분변 내 부티레이트 비율 감소가 관찰되었습니다 [36]. De Filippo 등[35]의 연구에서도 이탈리아 대상자가 단백질 풍부한 식단을 섭취했을 때 분변 SCFA가 적다는 유사한 결과를 보고했습니다. 흥미로운 임상적 연관성으로, 여러 연구에서 IBD 환자는 건강한 대상자보다 분변 내 Roseburia 및 기타 부티레이트 생성 세균의 수가 적다는 것이 입증되었습니다. 반면 건강한 대상자는 장내에 E. rectale이 10배 더 풍부합니다 [37–39].

이러한 장내 세균 변화는 대규모 참가자 전향적 연구(n = 67,581)에서 총 단백질 섭취량, 특히 동물성 단백질 섭취량이 IBD 위험 증가와 유의미하게 연관되었다는 결과와 관련될 수 있습니다 [40].

또한 적색 육류 섭취로 촉진되는 여러 미생물 속은 심혈관 질환 위험을 증가시키는 프로아테로겐성 화합물인 트리메틸아민-N-옥사이드(TMAO) 수치 증가와도 연관되어 있습니다 [41].

Fig. 2

Impact of dietary protein on intestinal microbiota and health outcomes. SCFA’s short chain fatty acids, TMAO trimethylamine N-oxide, Tregs T regulatory cells, CVD cardiovascular disease; IBD inflammatory bowel disease

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Table 2 Effects of protein on gut microbiota

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Mouse studies have revealed that high protein intake increases insulin-like growth factor 1 (IGF-1) levels, which are in turn associated with an increased risk of cancer, diabetes, and overall mortality. In one study, plant-derived proteins are associated with lower mortality than animal-derived proteins [42]. Accordingly, long-term practice of such dietary habits may increase risk of colonic disease and others. It is important to note that animal-based diets are often high in fat, in addition to protein. Dietary fat can also affect microbial composition; therefore, further studies will be required to investigate in what capacity each individual macromolecule impacts the bacterial communities and how they act in concert.

Fats

Consumption of high saturated and trans fat diets is thought to increase the risk of cardiovascular disease through upregulation of blood total- and LDL-cholesterol [43, 44]. On the other hand health-promoting fats, such as mono and polyunsaturated fats, are crucial in alleviating risk of chronic disease. The typical Western diet is both high in saturated and trans fats while low in mono and polyunsaturated fats, therefore predisposing regular consumers to many health problems [45–47]. Several human studies have suggested that a high-fat diet increases total anaerobic microflora and counts of Bacteroides [26, 29, 48, 49] (studies listed in Table 3). To specifically investigate the effects of different kinds of dietary fat on human gut microbiota, Fava et al. had subjects consume diets of varying fat content. The authors noted that consumption of a low fat diet led to increased fecal abundance of Bifidobacterium with concomitant reductions in fasting glucose and total cholesterol, compared to baseline. On the other hand, a high saturated fat diet increased the relative proportion of Faecalibacterium prausnitzii. Finally, subjects with high monounsaturated fat intake did not experience shifts in the relative abundance of any bacterial genera, but did have overall reduced total bacterial load and plasma total- and LDL-cholesterol [49]. In line with these findings, consumption of salmon–which is high in mono and polyunsaturated fats—was not noted to alter fecal microbiota composition in 123 subjects either [50]. Studies in rats have shown that intake of a high-fat diet results in considerably less Lactobacillus intestinalis and disproportionately more propionate and acetate producing species, including Clostridiales, Bacteroides, and Enterobacteriales. 

Furthermore, the abundance of Lactobacillus intestinalis is negatively correlated with rat fat mass and body weight [51]. Microbial changes have also been shown to control metabolic endotoxemia-induced inflammation in high-fat diet consuming mice [52]. Mouse studies have also compared the differential effects of various lipids on intestinal microflora. A comparison of lard-derived and fish oil-derived lipids revealed that Bacteroides and Bilophila were increased in lard-fed mice, while Actinobacteria (Bifidobacterium and Adlercreutzia), lactic acid bacteria (Lactobacillus and Streptococcus), and Verrucomicrobia (Akkermansia muciniphila) were increased in fish-oil-fed mice. Furthermore, lard-fed mice had increased systemic TLR activation, white adipose tissue inflammation, and impaired insulin sensitivity compared to mice consuming fish oil. The authors demonstrated that these findings are at least partly due to differences in gut microbiota between the two groups; transplantation of microbiota from one group to the other after antibiotic administration not only enriched the transplant recipient’s gut with dominant genera from the donor species, but also replicated the donor’s inflammatory and metabolic phenotypes. These results indicate that gut microbiota may promote metabolic inflammation through TLR signaling upon challenge with a diet rich in saturated lipids (Fig. 3) [53].

Fig. 3

Impact of dietary fats on intestinal microbiota and host metabolism. TLR toll-like receptor, WAT white adipose tissue, LDL low-density lipoprotein

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Table 3 Effects of fats on gut microbiota

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Carbohydrates

Digestible carbohydrates (starch, sugars)

Carbohydrates are possibly the most well studied dietary component for their ability to modify the gut microbiome (studies listed in Table 4). Carbohydrates exist in two varieties: digestible and non-digestible. Digestible carbohydrates are enzymatically degraded in the small intestine and include starches and sugars, such as glucose, fructose, sucrose, and lactose. Upon degradation, these compounds release glucose into the bloodstream and stimulate an insulin response [54]. Human subjects fed high levels of glucose, fructose, and sucrose in the form of date fruits [55] had increased relative abundance of Bifidobacteria, with reduced Bacteroides [56]. In a separate study, the addition of lactose to the diet replicated these same bacterial shifts while also decreasing Clostridia species. Notably, many Clostridium cluster XIVa species have been associated with irritable bowel syndrome [57, 58]. Lactose supplementation has additionally been observed to increase the fecal concentration of beneficial SCFAs [58]. These findings are quite unexpected given that lactose is commonly thought of as a potential gastrointestinal irritant (e.g. lactose intolerance). Further studies validating these observations can help clarify the effects of lactose.

Table 4 Effects of natural and artificial sugar on gut microbiota

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The artificial sweeteners saccharin, sucralose, and aspartame represent another dietary controversy. Artificial sweeteners were originally marketed as a health-conscious, no-calorie food option that could be used to replace natural sugar. Recent evidence from Suez et al. suggests that consumption of all types of artificial sweeteners is actually more likely to induce glucose intolerance than consumption of pure glucose and sucrose. Interestingly, artificial sweeteners are thought to mediate this effect through alteration of gut microbiota. For instance, saccharin-fed mice were noted to have intestinal dysbiosis with increased relative abundance of Bacteroides and reduced Lactobacillus reuteri [59]. These microbial shifts directly oppose those induced by intake of natural sugars (glucose, fructose, and sucrose)-as mentioned above. The evidence seems to suggest that, contrary to popular belief, artificial sweeteners may actually be unhealthier to consume than natural sugars.

Non-digestible carbohydrates (fiber)

In contrast to digestible carbohydrates, non-digestible carbohydrates such as fiber and resistant starch are not enzymatically degraded in the small intestine. Rather, they travel to the large intestine where they undergo fermentation by resident microorganisms. Accordingly, dietary fiber is a good source of “microbiota accessible carbohydrates” (MACs), which can be utilized by microbes to provide the host with energy and a carbon source [25, 60, 61]. In the process, they are able to modify the intestinal environment. This property of fibers warrants their additional designation as prebiotics, which by definition are non-digestible dietary components that benefit host health via selective stimulation of the growth and/or activity of certain microorganisms [62]. Sources of prebiotics include soybeans, inulins, unrefined wheat and barley, raw oats, and non-digestible oligosaccharides such as fructans, polydextrose, fructooligosaccharides (FOS), galactooligosaccharides (GOS), xylooligosaccharides (XOS), and arabinooligosaccharides (AOS) [63]. A diet that is low in these substances has been shown to reduce total bacterial abundance [64]. On the other hand, high intake of these carbohydrates in 49 obese subjects resulted in an increase in microbiota gene richness [30]. Regarding their effects on specific bacterial genera, many studies suggest that a diet rich in non-digestible carbohydrates most consistently increases intestinal bifidobacteria and lactic acid bacteria (studies listed in Table 5). The numerous studies listed in Table 5 corresponding to each type of prebiotic listed above, corroborate these findings. For instance, non-digestible carbohydrate diets that are rich in whole grain and wheat bran are linked to an increase in gut Bifidobacteria and Lactobacilli [65, 66]. Other non-digestible carbohydrates, such as resistant starch and whole grain barley, appear to also increase abundance of Ruminococcus, E. rectale, and Roseburia [3, 67, 68]. Additionally, FOS-, polydextrose-, and AOS-based prebiotics have been observed to reduce Clostridium [69–72] and Enterococcus species [73–76]. A cross-sectional study of 344 patients with advanced colorectal adenomas revealed that Roseburia and Eubacterium were significantly less preval‎ent, while Enterococcus and Streptococcus were more preval‎ent in these subjects compared to healthy controls. Reduced dietary fiber habits and consistently lower SCFA production were also observed in the adenoma group [77].

Table 5 Effects of non-digestible carbohydrates on gut microbiota

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In addition to their effects on the makeup of the microbiota, and likely partially mediated by these effects, prebiotics also produce notable shifts in metabolic and immune markers. For instance, several groups observed reductions in the proinflammatory cytokine IL-6, insulin resistance, and peak post-prandial glucose associated with intake of non-digestible carbohydrates present in whole grains [67, 78, 79]. One group additionally observed reductions in total body weight and concentrations of serum triglycerides, total cholesterol, LDL-cholesterol, and hemoglobin A1c [79]. West et al. [80] noted increased plasma levels of the anti-inflammatory cytokine IL-10 with consumption of butyrylated high amylose maize starch. The beneficial effect of prebiotics on immune and metabolic function in the gut is thought to involve increased production of SCFAs and strengthening of gastrointestinal-associated lymphoid tissue (GALT) from fiber fermentation [81].

Probiotics

Fermented foods containing lactic acid bacteria, such as cultured milk products and yogurt, represent a source of ingestible microorganisms that may beneficially regulate intestinal health and even treat or prevent inflammatory bowel disease [82]. They are thought to accomplish this through their effects on the existing gut microbiome (studies listed in Table 6), in addition to possible induction of anti-inflammatory cytokines such as IL-10 [83]. Based on these properties, foods enriched for these modulatory microorganisms are referred to as probiotics. Several groups have reported increased total bacterial load after regular consumption of fermented milk or yogurt [84–87]. Notable increases in beneficial gut Bifidobacteria and/or Lactobacilli have also consistently been observed with several different types of probiotics [85–97]. A randomized placebo-controlled trial of 60 overweight healthy adults fed probiotics containing three strains of Bifidobacteria, four strains of Lactobacilli, and one strain of Streptococcus reported significant increases in the concentration of total aerobes, anaerobes, Lactobacillus, Bifidobacteria, and Streptococcus compared to placebo. These subjects also had fewer total coliforms and Escherichia coli, as well as reduced triglycerides, total cholesterol, LDL-cholesterol, VLDL-cholesterol, and high-sensitivity C-reactive protein (hsCRP). HDL-cholesterol and insulin sensitivity improved after probiotic supplementation. Interestingly, the subjects with baseline low HDL, increased insulin resistance, and elevated hsCRP were noted to have significantly less total Lactobacilli and Bifidobacteria with more Escherichia coli and Bacteroides [98]. Probiotic-containing yogurt has also been shown to significantly reduce counts of the enteropathogens E. coli and Helicobacter pylori [94, 99].

Table 6 Effects of probiotics on gut microbiota

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Other reported health benefits from consuming fermented dairy products include alleviation of GI intolerance symptoms [86, 100–102], accelerated intestinal transit time [96], increase in total serum IgA to potentiate the humoral immune response [90, 93, 94, 103], inhibition of pathogen adhesion to intestinal mucosa [104], and decreased abdominal distention and ascites in chronic liver disease patients [99]. One study that analyzed stool from diarrhea-predominant IBS patients identified reduced abundance of Lactobacillus [105]. Interestingly, Lactobacilli and Bifidobacteria have actually been used successfully for the prophylactic prevention of traveller’s diarrhea [106].

Polyphenols

Dietary polyphenols, which include catechins, flavonols, flavones, anthocyanins, proanthocyanidins and phenolic acids, are actively studied for their antioxidant properties (studies listed in Table 7). Common foods with rich polyphenol content include fruits, seeds, vegetables, tea, cocoa products, and wine [107]. Commonly enriched bacterial genera amongst studies analyzing these food sources include Bifidobacterium and Lactobacillus [56, 108–114]. Relative abundance of Bacteroides also was reported to increase in subjects consuming red wine polyphenols [110, 115, 116]. Bifidobacterium are a commonly used probiotic strain with recorded health benefits such as immune-modulation, cancer prevention, and inflammatory bowel disease management [63]. In terms of further health benefits, consumption of cocoa-derived polyphenols has been associated with significant increases in plasma HDL and significant reductions in plasma triacylglycerol and C-reactive protein concentrations [112, 117]. Additionally, a study examining the antibacterial activity of fruit polyphenols found high sensitivity to these compounds in the enteropathogens Staphylococcus aureus and Salmonella typhimurium [118]. Moreover, reductions in pathogenic Clostridium species (C. perfringens and C. histolyticum) have been noted after consumption of fruit, seed, wine, and tea polyphenols [108, 112, 113, 119–122].

Table 7 Effects of polyphenols on gut microbiota

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Select diets

Several popular diets, including Western, gluten-free, omnivore, vegetarian, vegan, and Mediterranean, have been studied for their ability to modulate the intestinal microbiota (Fig. 4, studies listed in Table 8). In several studies, a Western diet (high in animal protein and fat, low in fiber) led to a marked decrease in numbers of total bacteria and beneficial Bifidobacterium and Eubacterium species [26, 29, 48]. Consumption of a Western diet has also been associated with production of cancer-promoting nitrosamines [123, 124].

Fig. 4

Impact of popular diets on intestinal microbiota and cardiometabolic disease. CVD cardiovascular disease, DM2 type 2 diabetes mellitus

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Table 8 Effects of special diets on gut microbiota

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Sanz et al. had 10 healthy subjects consume a gluten-free diet for 30 days. Populations of “healthy bacteria” decreased (Bifidobacterium and Lactobacillus), while populations of potentially unhealthy bacteria increased in parallel to reductions in polysaccharide intake after beginning the diet. In particular, increases were detected in numbers of E. coli and total Enterobacteriaceae, which may include further opportunistic pathogens [125]. Bonder et al. [126] similarly investigated the influence of a short-term gluten-free diet, noting reductions in Ruminococcus bromii and Roseburia faecis with increased Victivallaceae and Clostridiaceae.

Vegan and vegetarian diets are enriched in fermentable plant-based foods. One study compared vegan and vegetarian diets to an unrestricted control diet, and found that both vegans and vegetarians had significantly lower counts of Bifidobacterium and Bacteroides species [127] (p < 0.001). Interestingly, another study found a very modest difference in the gut microbomes of vegan versus omnivorous subjects [128]. The discrepancy between the two studies may be due to different methodologies for microbiome profiling (culture- vs sequencing-based), different control group diets, and/or host genetics. Future studies with careful experimental design will be needed to provide more insight into the differential effects of vegan and vegetarian diets on the gut microbiome.

Across the spectrum, the Mediterranean diet is highly regarded as a healthy balanced diet. It is distinguished by a beneficial fatty acid profile that is rich in both monounsaturated and polyunsaturated fatty acids, high levels of polyphenols and other antioxidants, high intake of fiber and other low glycemic carbohydrates, and relatively greater vegetable than animal protein intake. Specifically, olive oil, assorted fruits, vegetables, cereals, legumes, and nuts; moderate consumption of fish, poultry, and red wine; and a lower intake of dairy products, red meat, processed meat and sweets characterize the traditional Mediterranean diet [129]. De Filippis et al. investigated the potential benefits of the Mediterranean diet by comparing habitual omnivores, vegetarians, and vegans. They observed that the majority of vegans and vegetarians, but only 30% of omnivores, had high adherence to the Mediterranean diet. They detected significant associations between degree of adherence to the Mediterranean diet and increased levels of fecal SCFAs, Prevotella bacteria, and other Firmicutes. At the same time low adherence to the Mediterranean diet was associated with elevated urinary trimethylamine oxide, which is associated with increased cardiovascular risk [41]. Several other studies have shown that foods comprising the typical Mediterranean diet also improve obesity, the lipid profile, and inflammation. These changes may be mediated by diet-derived increases in Lactobacillus, Bifidobacterium, and Prevotella, and decreases in Clostridium [49, 110, 114, 130–132].

Discussion

The ability to rapidly identify and quantify gut bacterial genera has helped us understand the impact of diet on host microbial composition. Studies that involve intake of a specific dietary component demonstrate how certain bacteria tend to respond to the nutrient-specific challenge. Protein, fats, digestible and non-digestible carbohydrates, probiotics, and polyphenols all induce shifts in the microbiome with secondary effects on host immunologic and metabolic markers. For instance, animal protein intake positively correlates with overall microbial diversity, increases abundance of bile-tolerant organisms such as Bacteroides, Alistipes, and Bilophila, and reduces representation of the Roseburia/E. rectale group. A high-saturated fat diet seems to increase counts of total anaerobic microflora and the relative abundance of Bacteroides and Bilophila. Human studies have not reported that a high-unsaturated fat diet significantly alters the gut bacterial profile; however, mouse studies have reported increases in Actinobacteria (Bifidobacterium and Adlercreutzia), lactic acid bacteria (Lactobacillus and Streptococcus), and Verrucomicrobia (Akkermansia muciniphila). Both digestible and non-digestible carbohydrates are commonly reported in the literature to enrich Bifidobacterium and suppress Clostridia, while only non-digestible carbohydrates are noted to additionally enrich for Lactobacillus, Ruminococcus, Eubacterium rectale, and Roseburia. Lastly, both probiotics and polyphenols enhance Bifidobacterium and lactic acid bacteria, while reducing enteropathogenic Clostridia species.

Maintaining a healthy gut microbiome is critical to human health

An increasing body of evidence suggests that our gut microbiome has a profound impact on our health. In the past decade, gut microorganisms have been shown to play a role in a wide range of human diseases, including obesity, psoriasis, autism, and mood disorders [133–136]. The close relationship between diet, the gut microbiome, and health suggests that we may possibly improve our health by modulating our diet. One way in which microbiota can influence host health is by modulating host immunity. Studies in germ-free animals have demonstrated that the gut microbiome is essential for immune cell recruitment and differentiation [137]. Further investigations have revealed more specific roles for some bacterial species in mediating host immunity and immunologic diseases. In particular, the segmented filamentous bacteria have been found to promote autoimmune arthritis through an enhanced Th17 response [20, 138]. On the other hand, lactic acid bacteria and Bifidobacteria are known to secrete factors that dampen inflammation by downregulating NF-κB dependent gene expression‎, IL-8 secretion, and levels of macrophage-attracting chemokines [139]. Lactic acid bacteria and Bifidobacteria have also been shown to directly downregulate T effector-mediated inflammatory responses while upregulating anti-inflammatory T regulatory cell expression‎ in mice [140]. The exact mechanism of how these gut flora modulate immune responses is still not well understood; however, several studies suggest that microbial-derived SCFAs may be contributing via G-protein-coupled receptor and epigenetic mechanisms [141, 142]. Intestinal SCFAs have also been shown to directly increase the abundance of T regulatory cells in the gut and to protect against allergic airway inflammation [17, 143–145]. In addition, they may inhibit the transcription factor NF-κB, leading to decreased secretion of several pro-inflammatory cytokines [130]. Gut flora can also modulate host immunity through epigenetic modifications. For example, microbial-derived butyrate inhibits histone deacetylases 6 and 9, which leads to increased acetylation in the promoter of the FOXP3 gene and higher regulatory T cell proliferation [142]. Reduced methylation in the promoters of proinflammatory genes TLR2 and FFAR3 is correlated with reduced abundance of Faecalibacterium prausnitzii in type 2 diabetes patients [146, 147]. Clearly our gut microbiome has diverse effects on host immunity, and a balanced gut flora is critical for a healthy immune system (Table 9).

Table 9 Effects of dietary components on immune parameters

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Besides immunity, gut microorganisms have also been shown to impact host metabolic health. Individuals with metabolic disorders such as obesity and diabetes have been shown to have intestinal dysbiosis in relation to healthy individuals [148, 149]. Further characterization of the link between the gut microbiome and obesity has revealed several bacterial groups that may specifically contribute to the disease. In particular, obese individuals have a high baseline Firmicutes to Bacteroidetes ratio. In these subjects, reduction of caloric intake was noted to lower the Firmicutes to Bacteroidetes ratio [148]. Intriguingly, hosts with a gut microbiome dominated by Firmicutes have altered methylation in the promoters of genes that are linked to cardiovascular disease and obesity [150]. Additionally, Lactobacillus spp. have been shown to alleviate obesity-associated metabolic complications [151, 152]. The beneficial effects of Lactobacillus may be attributed to interactions with obesity-promoting bacteria in the gut and direct modulation of host immunity and gut barrier function [153]. Interestingly, the mucus-degrading bacteria A. muciniphila has also been linked to a healthy metabolic profile. Obese individuals with a higher baseline relative abundance of A. muciniphila tend to have greater improvements in obesity-associated metabolic parameters (insulin tolerance, plasma triglycerides and body fat distribution) after dietary intervention [154]. Interestingly, germ-free mice are more resistant to diet-induced obesity, possibly due to enhanced fatty acid metabolism in the absence of certain microflora [155]. Together, these findings demonstrate the important role of gut microbiota in maintaining host metabolic integrity (Table 10).

Table 10 Effects of dietary components on metabolic parameters

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Conclusion and future directions

In conclusion, review of the literature suggests that diet can modify the intestinal microbiome, which in turn has a profound impact on overall health. This impact can be beneficial or detrimental, depending on the relative identity and abundance of constituent bacterial populations. For example, it has been shown that a high-fat diet adversely reduces A. muciniphila and Lactobacillus, which are both associated with healthy metabolic states [53]. This observation provides a good example of how dietary intervention might potentially be used to manage complex diseases, such as obesity and diabetes. Furthermore, advances in microbiome research have suggested novel therapeutic possibilities for diseases that have traditionally been difficult to treat. For example, the fecal microbiota transplant has been used successfully to manage several different conditions, including ulcerative colitis, Clostridium difficile-associated colitis, irritable bowel syndrome, and even obesity [156–160]. It is possible that dermatologic conditions, including psoriasis and atopic dermatitis, may also be observed to benefit from re-engineering the gut microbiota. Recent advances in microbiome research offer exciting new tools to possibly enhance human health. Most of the studies reviewed in this manuscript profiled the microbiome using 16S rRNA amplicon sequencing, which utilizes the hypervariable regions of the bacterial 16S rRNA gene to identify bacteria present in biological samples. 16S rRNA sequencing is the most commonly used method by medical researchers to study microbial composition, due to its low cost and relatively easy workflow for sample preparation and bioinformatic analyses. However, 16S rRNA amplicon sequencing primarily provides information about microbial identity and not function. In order to investigate the microbiome’s functions, many researchers have turned to a shotgun metagenomic approach in which the whole bacterial genome is sequenced. Despite a higher cost and more complicated bioinformatics requirement, shotgun metagenomics provides information about both microbial identity and gene composition. Knowing which genes are encoded by the bacteria present in a sample allows researchers to better understand their roles in human health. With reducing costs of next generation sequencing, improved sample preparation protocols, and more bioinformatic tools available for metagenomic analysis, this technique will be a powerful tool to study microbiome functionality. Performing meta-analyses to correlate the microbiome with host genomes, transcriptomes, and immunophenotypes represents another exciting avenue for investigating human and bacterial interactions.

Precision medicine is another attractive, novel therapeutic approach for many diseases with strong genetic associations. It is important to note that the host genotype also plays a role in shaping the microbiome, and that this host-microbe interaction is crucial for maintaining human health [161]. Therefore, a better understanding of the interplay between genes, phenotypes, and the microbiome will provide important insights into the utility of precision medicine.

The observation that diet can modulate host-microbe interactions heralds a promising future therapeutic approach. Already, the gut microbiome has been found to influence the response to cancer immunotherapy [162, 163]. Indeed, personalized nutrition is an emerging concept that utilizes a machine-learning algorithm to predict metabolic responses to meals [164, 165]. This tool has broad implications for individualized patient care through dietary modification. While this and other technology is in the process of being refined and validated, further research using large, long-term clinical trials to eval‎uate a greater variety of food components would be helpful in making specific dietary recommendations to patients.

Abbreviations

AOS:

arabinooligosaccharides

FOS:

fructooligosaccharides

GALT:

gut-associated lymphoid tissue

GOS:

galactooligosaccharides

HDL:

high-density lipoprotein

hsCRP:

high-sensitivity C-reactive protein

IBD:

inflammatory bowel disease

IBS:

irritable bowel syndrome

IGF:

insulin-like growth factor-1

LDL:

low-density lipoprotein

MAC:

microbiota accessible carbohydrate

TLR:

toll-like receptor

TMAO:

trimethylamine-N-oxide

VLDL:

very low-density lipoprotein

XOS:

xylooligosaccharides

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