Collateral damage: microbiota-derived metabolites and immune function in the antibiotic era

Abstract

Our long-standing evolutionary association with gut-associated microbial communities has given rise to an intimate relationship, which affects many aspects of human health. Recent studies on the mechanisms that link these microbial communities to immune education, nutrition, and protection against pathogens point to microbiota-derived metabolites as key players during these microbe-host interactions. A disruption of gut-associated microbial communities by antibiotic treatment can result in a depletion of microbiota-derived metabolites, thereby enhancing pathogen susceptibility, impairing immune homeostasis, and contributing to the rise of certain chronic inflammatory diseases. Here, we highlight some of the recently elucidated mechanisms that showcase the impacts of microbiota-derived metabolites on human health.

Figure 1

Microbial products induce mucosal barrier functions. Concomitant activation of TLR5 during presentation of flagellin by antigen presenting cells (APC) renders flagellin a dominant B cell antigen. Flagellin-specific immunoglobulin A (IgA) helps control motile bacteria in the gut lumen. Indole derivatives (tryptamine, indole 3-acetate and indole) are produced by the gut microbiota during the break down of indigestible proteins. These metabolites induce the release of IL-22 by activating the aryl hydrocarbon receptor (AHR) on host cells. IL-22 stimulates epithelial cells to release antimicrobial proteins (such as RegIIIβ, RegIIIγ, lipocalin-2, and calprotectin) that help control luminal bacteria.

Figure 2

Maintenance of immune homeostasis by microbiota-derived metabolites. Digestion of dietary fiber leads to an accumulation in the gut lumen of microbiota-derived metabolites that have anti-inflammatory properties. Activation of the SCFA receptor PPAR-γ inhibits pro-inflammatory responses by inhibiting NF-κB activation. SCFAs cause an expansion of regulatory T cells through mechanisms that depend on SCFA receptors GPR43 and GPR109A. In turn, regulatory T cells maintain gut homeostasis by resolving inflammation through inhibition of effector T cell function and increasing production of IL-10. SCFAs can enter the circulation and enhance the generation of APC precursors in the bone marrow through a GPR41-dependent mechanism. After seeding the lung, APCs generated through this process exhibit a reduced ability to promote T helper type 2 (T_H2) cell effector function, thereby conferring protection from allergic airway inflammation.