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Review
. 2020 Aug 18;53(2):264-276.
doi: 10.1016/j.immuni.2020.07.015.

Deconstructing Mechanisms of Diet-Microbiome-Immune Interactions

Affiliations
Review

Deconstructing Mechanisms of Diet-Microbiome-Immune Interactions

Margaret Alexander et al. Immunity. .

Abstract

Emerging evidence suggests that the effect of dietary intake on human health and disease is linked to both the immune system and the microbiota. Yet, we lack an integrated mechanistic model for how these three complex systems relate, limiting our ability to understand and treat chronic and infectious disease. Here, we review recent findings at the interface of microbiology, immunology, and nutrition, with an emphasis on experimentally tractable models and hypothesis-driven mechanistic work. We outline emerging mechanistic concepts and generalizable approaches to bridge the gap between microbial ecology and molecular mechanism. These set the stage for a new era of precision human nutrition informed by a deep and comprehensive knowledge of the diverse cell types in and on the human body.

Keywords: host receptors; immunology; metabolites; microbiome; nutrition.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. General types of interactions between diet, microbiota, and immune responses.
(A) (Black) The immune system shapes the microbiota, which alters the metabolism of immunomodulatory dietary factors. (Red) The microbiota metabolizes dietary substrates into immunomodulatory metabolites. (Orange) Diet influences the microbiota resulting in altered immune responses. (Blue) Dietary factors are metabolized by the host resulting in alterations to immunomodulatory microbes. (B-G) General mechanisms by which the diet, microbiome, and immune system interact to induce immunological changes: (B) Dietary derived microbial metabolites alter immune response via host receptor signaling; (C) Diet alters the fitness of immunomodulatory microbes; (D) Diet alters microbiome composition and activity, which modulates the immune response; (E) Diet alters host metabolite production which impacts immunomodulatory microbes; (F) Microbes shape host metabolism of immunomodulatory dietary factors; and (G) The immune system shapes the microbiome altering microbial metabolism of immunomodulatory dietary factors.
Figure 2.
Figure 2.. Diet alters the immunomodulatory potential of the gut microbiota.
(A) Mice on a fasting mimicking diet have reduced blood lymphocytes and C reactive protein, which corresponds to alterations in the composition of the gut microbiota. Transplantation of this altered microbiota into germ-free (GF) donor mice phenocopies the donor mice and results in improved dextran sodium sulfate (DSS) colitis response (Rangan et al., 2019). (B) Resistant starch is metabolized by members of the gut microbiota into the short chain fatty acid (SCFA) butyrate which has direct effects on immune responses, such as the increased antimicrobial activity of macrophages (Schulthess et al., 2019). Additionally, butyrate can directly inhibit growth of L. reuteri, which has been shown to worsen lupus severity in a mouse model (Zegarra-Ruiz et al., 2019). (C) The growth of L. murinus is inhibited in vitro by increasing salt (NaCl) concentrations. Mice on a high salt diet supplemented with L. murinus had reduced Th17 levels and less severe disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (Wilck et al., 2017).
Figure 3.
Figure 3.. Diet alters production of host and microbial metabolites feeding back on immune responses.
(A) Mice fed a milk fat diet had increased levels of hepatic taurine conjugation of bile acids, which was associated with a bloom in B. wadsworthia. Supplementation of mice on a low-fat diet with taurocholic acid resulted in increased levels of B. wadsworthia, Th1 cells, and higher incidence of colitis in Il10−/− mice (Devkota et al., 2012). (B) Mice on a nutrient rich diet compared to a nutrient poor (minimal) diet have different compositions of primary and secondary bile acid (BA) pools. Bile salt hydrolase enzymes along with other microbial enzymes are involved in the production of secondary bile acids from primary bile acids (Yao et al., 2018). Secondary bile acids can alter immune responses via their interactions with immune receptors such as the nuclear receptors vitamin D receptor (VDR) and farnesoid X receptor (FXR) (Song et al., 2020) and the Th17 cell master transcription factor Rorγt (Hang et al., 2019). For example, 3-oxo-lithocholic acid (3-oxo-LCA) directly binds and inhibits Rorγt resulting in decreased levels of CD4+IL-17A+ Th17 cells (Hang et al., 2019).
Figure 4.
Figure 4.. The gut microbiota alters the metabolism of immunomodulatory dietary factors and immune responses alter immunomodulatory bacteria.
(A) Members of the Clostridia class inhibit the expression of retinol dehydrogenase 7 (Rdh7) in intestinal epithelial cells (IECs) (Grizotte-Lake et al., 2018). Rdh7 is responsible for metabolizing vitamin A into retinoic acid (RA). RA promotes the production of IL-22, which induces antimicrobial peptides (AMPs) -Reg3γ, Reg3B, S100A8, S100A9. These AMPs suppress the growth of gut microbiota. The inhibition of members of the gut microbiota by AMPs may contribute to the reduction of colonization resistance to Salmonella typhimurium. (B) Caspase Recruitment Domain-containing protein 9 (CARD9) is an important immune signalling protein involved in fungal immune responses. Card9/ mice have decreased levels of the gut bacterium L. reuteri suggesting Card9 promotes L. reuteri colonization. L. reuteri metabolizes tryptophan into indole-3-acetic acid (IAA) which is an aryl hydrocarbon receptor (AHR) agonist (Lamas et al., 2016). AHR activation results in IL-22 production, among other things.

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