Gut microbiota, metabolites and host immunity

Abstract

The microbiota - the collection of microorganisms that live within and on all mammals - provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host-microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system.

Figure 1. SCFAs, GPCRs, host physiology and immunity

Short-chain fatty acids (SCFAs)—such as butyric acid, propionic acid and acetic acid — are produced by colonic microbial fermentation of undigested or partially digested dietary fibres and have broad effects on host immune system development and function. SCFAs bind G protein-coupled receptors (GPCRs), such as GPR41, GPR43 and GPR109A, on the surface of epithelial cells and immune cells (not shown). Transport or diffusion of SCFAs into host cells results in their metabolism and/or inhibition of histone deacetylase (HDAC) activity. The effects of SCFAs are manifold and include enhanced epithelial barrier function and immune tolerance, which promote gut homeostasis through specific mechanisms: enhanced production of mucus by intestinal goblet cells; inhibition of nuclear factor-κB (NF-κB); activation of inflammasomes and subsequent production of interleukin-18 (IL-18); increased secretion of secretory IgA (sIgA) by B cells; reduced expression of T cell-activating molecules on antigen-presenting cells, such as dendritic cells (DCs); and increased number and function of colonic regulatory T (T_reg) cells, including their expression of forkhead box P3 (FOXP3) and their production of anti-inflammatory cytokines (transforming growth factor-β (TGFβ) and IL-10). SCFAs also reach other organs, such as the brain and lungs, in which they directly or indirectly act on local or resident antigen-presenting cells to decrease inflammatory responses that are associated with neuroinflammation and allergic airway disease, respectively.

Figure 2. Immune modulation by the microbial components PSA, formyl peptides and HBP

So far, several bacterial factors that engage non-canonical pattern recognition receptors (PRRs) have been identified, including polysaccharide A (PSA), formyl peptides and D-glycero-β-D-manno-heptose-1,7-biphosphate (HBP). a | PSA from Bacteroides fragilis can alter the CD4⁺ T helper 1 (T_H1)-T_H2 cell balance in the spleen (not shown) and shift the balance of effector T cell subsets in the periphery. In the gut, PSA is taken up by lamina propria dendritic cells (DCs), and processed and presented to naive CD4⁺ T cells. Activated transforming growth factor-β(TGFβ) induces the expansion of anti-inflammatory forkhead box P3 (FOXP3)⁺ regulatory T (T_reg) cells and the production of interleukin-10 (IL-10), which suppress the activity of inflammatory T_H1 and T_H17 cells. b | Formyl peptides released by all bacteria bind formyl peptide receptors (FPRs), which are G protein-coupled receptors that are found on neutrophils and other immune cells. Formyl peptides from Staphylococcus aureus can signal through FPR1 and contribute to the activation of nociceptor-driven mechanical pain and the release of immunosuppressive neuropeptides. At high nanomolar concentrations, S. aureus-derived formyl peptides that are known as phenol-soluble modulins (PSMs) stimulate massive neutrophil influx to infection sites by binding to FPR2. Induced neutrophil activation leads to an oxidative burst. PSMs affect the adaptive immune system by inducing a tolerogenic phenotype in DCs and inhibiting the differentiation of T_H1 cells. S. aureus can also use PSMs to escape from phagolysosomes, lyse host cells and disperse biofilms, and can also kill competing bacteria (not shown). c | HBP is a monosaccharide that is generated during lipopolysaccharide (LPS) biosynthesis by Gram-negative bacteria and detected in the cytosol of host cells. HBP that is secreted by the extracellular pathogen Neisseria gonorrhoeae induces innate and adaptive immune responses by phosphorylation-dependent oligomerization of TIFA (TRAF-interacting protein with FHA domain-containing protein A). Activation of TIFA and its subsequent interaction with TNF receptor-associated factor 6 (TRAF6) leads to TRAF6 ubiquitin (Ub)-dependent activation of nuclear factor-κB (NF-κB), which induces the expression of pro-inflammatory immune genes. IFNγ, interferon-γ; P, phosphate; TCR, T cell receptor.