Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity
Hassan Melhem, Berna Kaya, Tanay Kaymak, Philipp Wuggenig, Emilio Flint, Julien Roux, Koen C. Oost, Claudia Cavelti‐Weder, Maria L. Balmer, Jean‐Claude Walser, Rodrigo A. Morales, Christian U. Riedel, Prisca Liberali, Eduardo J. Villablanca, Jan Hendrik Niess
Abstract
Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell-type-specific deletion of Gpr35 in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota. Goblet cells through their production and secretion of mucins play an essential role in protecting the host against luminal insults, and contribute to the mutualism between host and gut microbiota. Loss of epithelial Gpr35 disrupts the goblet cell compartment by reducing their numbers and increasing pyroptosis levels. Dysregulation of goblet cells is correlated with changes in the mucosa-associated bacterial communities. As a result, Gpr35f/fVil+ mice displayed increased susceptibility to C. rodentium-induced colitis. (Adapted from SERVIER MEDICAL ART (CC of license 3.0)).