The role of gut metabolites on regulation of intestinal immunity

Myunghoo Kim, Purdue University

Abstract

The gastrointestinal tract contains multiple types of immune cells that induce various immune responses to dietary antigens, commensal bacteria, and pathogens. Maintaining homeostasis at this mucosal barrier requires stringent regulation of the immune responses, including mechanisms to convey information about environmental conditions. Dietary nutrients can be converted into gut metabolites through either host or microbial enzymatic activities. Accumulating evidence demonstrates that these gut metabolites have a significant impact on the regulation of intestinal immune responses; however, the underlying mechanisms by which gut metabolites regulate the intestinal immune system are incompletely understood. Thus, we have studied the role of gut metabolites, specifically short chain fatty acids (SCFAs) and retinoic acid (RA), in regulation of intestinal immune responses. Our research revealed novel pathways that SCFAs and RA use to contribute to anti-bacteria immunity through modulation of epithelial cells and innate lymphoid cells (ILCs), respectively. SCFAs are the major metabolites of dietary fibers and produced from microbial fermentation in the colon. A mounting body of evidence indicates that SCFAs regulate cells in the immune system to promote aspects of both immunity and immune tolerance. We investigated regulation of the intestinal inflammatory responses by SCFAs and their receptors, GPR41 and GPR43. The control and SCFA-fed wild type (WT), GPR41-/-, and GPR43 -/- mice were chemically challenged with ethanol and 2, 4, 6-trinitrobenzene sulfonic-acid (TNBS) or infected with Citrobacter rodentium to gain insights on the roles of SCFA signaling in inflammatory responses. From these in vivo studies, we reported that GPR41 -/- and GPR43-/- mice had abnormally hypo-inflammatory responses following chemical challenges. They also had a delayed immune response in clearing C. rodentium compared to WT mice. SCFA treatment caused intestinal epithelial cells (ECs) to produce inflammatory mediators both in vitro and in vivo in a GPR41- and GPR43-dependent manner. These processes were necessary to recruit neutrophils and induce effector T cells differentiation in the intestine after immune challenges. The underlying mechanism is that SCFA receptors activated extracellular signal-regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways in ECs for production of inflammatory cytokines and chemokines. Separately, we studied the role of the gut metabolite, RA, in regulating innate immunity in the intestine. RA is a vitamin A metabolite known to regulate various immune responses, including development, function, and migration of lymphocytes in the intestine. However, the roles of RA in innate lymphocyte biology are insufficiently defined. We identified a novel function of RA in the migration program of ILCs, a class of newly identified innate lymphocytes to the gut. This regulatory function of RA has a significant impact on anti-bacterial immunity in the gut. We reported that intestinal ILCs must undergo a ‘homing receptor (HR) switch’ from a secondary lymphoid tissue receptor (CCR7) to gut homing receptors (CCR9 and ?4?7) to migrate to the intestine. Mucosal dendritic cells (DCs)-derived RA induced this HR switch, which is required for effector function of ILCs in the intestine. However, the RA-mediated HR switch occurred only in ILC1 and ILC3 subsets, but not ILC2s. In contrast, ILC2s acquired gut HRs during their development in the bone marrow and BM ILC2 precursors could migrate directly to the intestine. Vitamin A deficient (VAD) mice exhibited higher susceptibility to C. rodentium infection with decreased ILC3 numbers in the gut compared to mice fed vitamin A normal diet (VAN). We demonstrated that efficient anti-pathogenic bacterial immunity in the intestine requires RA-induced gut HRs expression in ILC3s.

Degree

Ph.D.

Advisors

Kim, Purdue University.

Subject Area

Immunology

COinS