TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis

Compartmentalization of Toll‐like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a , a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell‐intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild‐type controls, germ‐free Rab11a‐deficient mouse intestines failed to tolerate the intraluminal stimulation of microbial agonists. Thus, Rab11a endosome controls intestinal host‐microbial homeostasis at least partially via sorting TLRs. Synopsis Immunologic tolerance to intestinal microbiota depends on Rab11 endosome‐mediated control of pathogen pattern recognition receptor TLR9 processing and signaling. Loss of Rab11a in enterocytes causes cell‐autonomous inflammatory cytokine production and crypt cell proliferation. Rab11a endosomes control Toll‐like receptor distribution and processing in intestinal epithelial cells. Rab11a endosome‐mediated host–microbial homeostasis is conserved in flies and mammals. Graphical Abstract Immunologic tolerance to intestinal microbiota depends on Rab11 endosome‐mediated control of pathogen pattern recognition receptor TLR9 processing and signaling.