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Cited by 2,257Gut microbiota and healthNutrition, Genetics, and DiseaseNutritional Studies and Diet

Diet–microbiota interactions as moderators of human metabolism

Open access
Sonnenburg, Justin L., Bäckhed, Fredrik·2016·Nature
DOI 10.1038/nature18846PMC PMC5991619
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Abstract

It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with obesity are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships in people and the prospect of therapeutic interventions such as personalized nutrition.

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Crossref · 10.1038/nature18846

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  • Premisecitation

    Microbiota from genetically obese mice can increase adiposity when transplanted into lean mice.

    “The altered microbiota that is observed in genetically obese mice11,12 is sufficient to promote increased adiposity in lean mice that receive a microbiota transplant12”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Germ-free mice are protected from diet-induced obesity when fed a Western-style diet.

    “Germ-free mice are protected from diet-induced obesity when fed a Western-style diet8–10”
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    Obesity is associated with reduced diversity of the gut microbiota.

    “The picture that is emerging suggests that obesity is associated with reduced diversity of the gut microbiota13,17.”
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  • Premisecitation

    Long-term dietary habits are a dominant determinant of an individual's gut microbiota composition.

    “long-term dietary habits are a dominant force in determining the composition of an individual’s gut microbiota”
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    Diet modulates the composition and function of the gut microbiota in humans and other mammals.

    “diet modulates the composition and function of this community of microbes in humans and other mammals18–25”
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    Premisecitation

    Germ-free mice have lower adiposity and better glucose and insulin tolerance than colonized mice.

    “germ-free mice, which lack a microbiota, have reduced adiposity and improved tolerance to glucose and insulin when compared with conventional (colonized) counterparts7”
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    • cites [7] Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004). source

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    Ruminococcus bromii-related taxa bloomed in response to resistant starch in most of 14 obese men; non-response may reflect absence of those taxa.

    “Ruminococcus bromii-related taxa bloomed in response to resistant-starch intervention in most of the 14 obese men in one study; the lack of response in the other individuals might reflect an absence of such taxa in those people23.”
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    Premisecitation

    The presence of microbiota is necessary and sufficient for obesity in mice; transferring microbiota from Western-diet-fed mice to germ-free mice transfers the obese phenotype.

    “The presence of the microbiota is both necessary and sufficient for obesity: the transfer of microbiota from mice fed a Western diet to germ-free mice transfers the obese phenotype43.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Interpretationreasoning

    People who eat large amounts of plants, such as some African communities with up to sevenfold higher fibre intake, probably generate more short-chain fatty acids that contribute more to whole-body energy needs.

    “people who eat large quantities of plants, the main source of dietary fibre38, such as those in certain African communities that consume up to sevenfold more fibre than people the industrialized world39, might generate considerably more short-chain fatty acids, which therefore probably contribute more to the whole-body energy requirement.”
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    Premisecitation

    Mouse microbiota suppress intestinal Angptl4 expression, increasing lipoprotein lipase activity in adipose tissue and promoting fat storage.

    “The microbiota of mice suppress the expression of intestinal angiopoietin-like protein 4, an inhibitor of the enzyme lipoprotein lipase, which increases lipoprotein-lipase activity in adipose tissue and promotes the storage of fat7.”
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    • cites [7] Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004). source

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    Interpretationreasoning

    Industrialization has been accompanied by an overall decline in gut microbiota biodiversity and loss of specific phylogenetic groups, potentially due to modern lifestyles, medical practices, and processed foods.

    “industrialization has been accompanied by an overall decline in gut microbiota biodiversity as well as the loss of specific phylogenetic groups — a potential consequence of modern lifestyles, medical practices and processed foods.”
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    Premisecitation

    Saturated and unsaturated fats have different effects on gut microbiota; microbiota altered by unsaturated fats can protect against lard-induced weight gain.

    “Saturated and unsaturated fats have profoundly different effects on the gut microbiota, and the altered microbiota that results from feeding unsaturated fats can offer protection from lard-induced weight gain44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Germ-free mice have reduced adiposity despite increased food intake compared with colonized mice, indicating that the microbiota aids energy extraction from food.

    “germ-free mice have a reduced adiposity despite an increased intake of food by comparison with their colonized counterparts7, which demonstrates that the microbiota helps to extract energy from food.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004). source

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    Premisecitation

    High biodiversity does not always indicate a health-promoting ecosystem; bacterial vaginosis has greater diversity than a healthy state.

    “a high level of biodiversity does not always correspond to a health-promoting ecosystem: for example, bacterial vaginosis is characterized by a diversity greater than that observed in a healthy state59.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    A microbiota-encoded porphyran degradation system is rare in Western people but common in populations that regularly eat seaweed.

    “a microbiota-encoded degradation system for porphyran, a polysaccharide that is found in certain species of edible seaweed, is rare in the microbiotas of Western people but prominent in those of populations that regularly consume seaweed29.”
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    • cites [29] Hehemann, J. H. et al. Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota. Nature 464, 908–912 (2010). source

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    Premisecitation

    In mice, blocking the microbial enzyme TMA lyase lowers circulating TMAO and prevents atherosclerosis.

    “An inhibitor of TMA lyase that stops the microbial synthesis of TMA and therefore reduces the levels of circulating TMAO prevents the development of atherosclerosis in mice121.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). The first example of inhibiting microbial enzymes (or 'drugging the bug') to prevent atherosclerosis. source

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    Premisecitation

    A machine-learning model combining microbiome, metabolic, and behavioural data predicted how a person's blood glucose would respond to a specific food, and this held in a separate cohort.

    “However, when compared with microbiome profiles and with measurements of metabolism and behaviour, using a machine-learning approach, the response of an individual to a given food could be predicted — even in an independent cohort.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015). This study used a machine-learning approach to mine personal health profiles that included microbiome data to predict the postprandial glycaemic response. source

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    Premisecitation

    The majority of human and mouse research uses stool samples, which only partly reflect conditions along the digestive tract.

    “The majority of studies in humans and mice rely on faecal samples, which provide some representation of what is occurring throughout the digestive tract”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [119] Lichtman, J. S. et al. The effect of microbial colonization on the host proteome varies by gastrointestinal location. ISME J. 10, 1170–1181 (2016). source

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    Premisecitation

    Among 800 participants, blood glucose responses after eating specific foods varied widely.

    “One study used continuous blood-glucose monitoring to follow postprandial glycaemic responses in 800 people114.”
    • Also stated in: § Dietary interventions and diet-based therapeutics · plain
      “The responses of individuals to particular foods were highly variable.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Zeevi, D. et al. Personalized nutrition by prediction of glycemic responses. Cell 163, 1079–1094 (2015). This study used a machine-learning approach to mine personal health profiles that included microbiome data to predict the postprandial glycaemic response. source

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    Premisecitation

    Giving these mice a peanut-based ready-to-use therapeutic food led to a brief rise in weight and a return of their microbiota toward normal.

    “when the mice are fed a peanut-based, ‘ready-to-use’ therapeutic food, their weight transiently increases and their microbiota normalize115.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Germ-free mice receiving microbiota from obese people gained more weight, reproducing the obese phenotype, whereas giving them Christensenella minuta blocked weight gain.

    “In one-such study, transplantation of the microbiota from obese individuals to germ-free mice transfers the obese phenotype, as determined by increased weight gain, whereas administration of Christensenella minuta prevents weight gain15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014). source

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    Premisecitation

    IL-22 prompts epithelial cells to make SAA1 and SAA2 in a paracrine manner, which is needed to activate ileal TH17 cells.

    “which subsequently induces the production of the proteins serum amyloid A1 and serum amyloid A2 from the epithelium in a paracrine fashion — a process that is required for the activation of TH17 cells in the ileum113.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 163, 381–393 (2015). source

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    Premisecitation

    In mice, Prevotella benefits glucose metabolism only if the diet supplies fermentable fibre/polysaccharides; it does not do so on a high-fat or Western-style diet lacking them.

    “Prevotella could also improve the glucose metabolism of mice that were fed carbohydrate-rich diets but not a high-fat diet that was devoid of fermentable polysaccharides.”
    • Also stated in: § Perspective · hedged
      “supplementation with Prevotella produces an improved tolerance to glucose only when mice are fed a standard diet that is rich in fibre, and not a Western-style diet, which is devoid of fibre22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Kovatcheva-Datchary, P. et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of Prevotella. Cell Metab. 22, 971–982 (2015). source

      Not checked in the free run.

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    Premisecitation

    The microbiota of obese people had more genes for making branched-chain amino acids, and these genes correlate with poorer insulin sensitivity.

    “the microbiota of obese individuals had an increased abundance of genes that are involved in biosynthesis of branched-chain amino acids, which are associated with impaired sensitivity to insulin14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013). This study showed that a microbiota from a lean individual could invade the microbiota of an obese individual and provide protection from weight gain, but that the invasion and protection was dependent on diet. source

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    Premisecitation

    In a multigenerational mouse study, a Western-style diet worsened loss of microbiota diversity compared with a diet rich in microbiota-accessible carbohydrates, and taxon extinction corresponded with predicted loss of glycoside hydrolase diversity.

    “In a multigenerational study in mice, the consumption of a Western-style diet exacerbated the loss of microbiota diversity compared with a diet that was rich in microbiota-accessible carbohydrates, and the extinction of taxa corresponded with a predicted loss in diversity of glycoside hydrolases63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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  • The paper relies on this without support.

    Findings from animal models about microbiota and metabolism are relevant to human metabolic health.

    “Mechanisms that link the gut microbiota with obesity are coming to light through a powerful combination of translation-focused animal models and studies in humans.”

  • The paper relies on this without support.

    The gut microbiota is a powerful means of influencing human health.

    “The gut microbiota provides a powerful route to influencing human health.”

  • The paper relies on this without support.

    Diet, especially polysaccharides, primarily controls the composition and function of the gut microbiota.

    “Diet and, in particular, polysaccharides serve as primary modulators of the composition and function of the microbiota.”

  • The paper relies on this without support.

    Microbial metabolites likely mediate host metabolism and may be beneficial or harmful.

    “Microbial metabolites probably act as mediators for the host metabolism and can be either beneficial (for example, butyrate) or detrimental (TMAO).”

  • The paper relies on this without support.

    A single metabolite is unlikely to be solely responsible for promoting or preventing metabolic diseases.

    “it is unlikely that one metabolite acts alone to promote or prevent metabolic diseases.”
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  1. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009). · DOI · Paper page

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Authors
Sonnenburg, J. L., & Bäckhed, F.
Affiliations
  • Stanford Medicine (US)
  • University of Copenhagen (DK)
Corresponding author
  • Sonnenburg, Justin L.
  • Bäckhed, Fredrik
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2016-07-06
Volume
535
Issue
7610
Pages
56-64
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature18846
PMC
PMC5991619
OpenAlex
W2465534016
Cited by
2,257
References
135
Citations by year
2026: 191 · 2025: 203 · 2024: 234 · 2023: 219 · 2022: 287 · 2021: 286 · 2020: 242 · 2019: 200 · 2018: 204 · 2017: 166 · 2016: 24
FWCI
17.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Novo Nordisk Fonden (NNF13OC0008163)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085025)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
gut microbiota, obesity, type 2 diabetes, metabolic disorders, host metabolism, animal models, causal relationship, personalized nutrition, therapeutic interventions
MeSH terms
Gastrointestinal Microbiome, Animals, Diabetes Mellitus, Type 2, Diet, Fatty Acids, Humans, Inflammation, Metabolic Diseases, Metabolism, Obesity, Signal Transduction, Precision Medicine

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