Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation

Brinda Bhatt, Peng Zeng, Huabin Zhu, Sathish Sivaprakasam, Siyi Li, Haiyan Xiao, Lixin Dong, Shyang-Yun Pamela Shiao, Ravindra Bharat Kolhe, Honglin Li, Daniel Levy Bercowski, Vadivel Ganapathy, Nagendra Singh, Nikhil Patel

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 Gpr109a 2 / 2 Rag1 2 / 2 mice exhibit spontaneous rectal prolapse and colonic inflammation, characterized by the presence of an elevated number of IL-17–producing Rorgt + innate lymphoid cells (ILCs; ILC3). Genetic deletion of Rorgt alleviated the spontaneous colonic inflammation in Gpr109a 2 / 2 Rag1 2 / 2 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 Gpr109a 2 / 2 Rag1 2 / 2 mice. The ceca of Gpr109a 2 / 2 Rag1 2 / 2 mice showed significantly increased colonization by members of Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Streptococcaceae, Christensenellaceae, and Mogibacteriaceae, as well as IBD-associated microbiota such as Enterobacteriaceae and Mycoplasmataceae, compared with Rag1 2 / 2 mice, housed in a facility positive for Helicobacter 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.

Original languageEnglish (US)
Pages (from-to)2905-2914
Number of pages10
JournalJournal of Immunology
Volume200
Issue number8
DOIs
StatePublished - Apr 15 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Gpr109a limits microbiota-induced IL-23 production to constrain ILC3-mediated colonic inflammation'. Together they form a unique fingerprint.

Cite this