Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation

Abstract

A set of coordinated interactions between gut microbiota and the immune cells surveilling the intestine play a key role in shaping local immune responses and intestinal health. Gpr109a is a G protein-coupled receptor expressed at a very high level on innate immune cells and previously shown to play a key role in the induction of colonic regulatory T cells. In this study, we show that <i>Gpr109a^-/-Rag1^-/-</i> mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17-producing Rorγt⁺ innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorγt alleviated the spontaneous colonic inflammation in <i>Gpr109a^-/-Rag1^-/-</i> mice. Gpr109a-deficient colonic dendritic cells produce higher amounts of IL-23 and thereby promote ILC3. Moreover, the depletion of gut microbiota by antibiotics treatment decreased IL-23 production, ILC3, and colonic inflammation in <i>Gpr109a^-/-Rag1^-/-</i> mice. The ceca of <i>Gpr109a^-/-Rag1^-/-</i> mice showed significantly increased colonization by members of <i>Bacteroidaceae</i>, <i>Porphyromonadaceae</i>, <i>Prevotellaceae, Streptococcaceae</i>, <i>Christensenellaceae</i>, and <i>Mogibacteriaceae</i>, as well as IBD-associated microbiota such as <i>Enterobacteriaceae</i> and <i>Mycoplasmataceae</i>, compared with <i>Rag1^-/-</i> mice, housed in a facility positive for <i>Helicobacter</i> and murine norovirus. Niacin, a Gpr109a agonist, suppressed both IL-23 production by colonic DCs and ILC3 number in a Gpr109a-dependent manner. Collectively, our data present a model suggesting that targeting Gpr109a will be potentially beneficial in the suppression of IL-23-mediated immunopathologies.