Clec12a controls colitis by tempering inflammation and restricting expansion of specific commensals

Microbiota composition regulates colitis severity, yet the innate immune mechanisms that control commensal communities and prevent disease remain unclear. We show that the innate immune receptor, Clec12a, impacts colitis severity by regulating microbiota composition. Transplantation of microbiota from a Clec12a−/− animal is sufficient to worsen colitis in wild-type mice. Clec12a−/− mice have expanded Faecalibaculum rodentium, and treatment with F. rodentium similarly exacerbates disease. However, Clec12a−/− animals are resistant to colitis development when rederived into an 11-member community, underscoring the role of specific species. Colitis in Clec12a−/− mice is dependent on monocytes, and cytokine and sequencing analysis in Clec12a−/− macrophages and serum shows enhanced inflammation with a reduction in phagocytic genes. F. rodentium specifically binds to Clec12a, and Clec12a−/−-deficient macrophages are impaired in their ability to phagocytose F. rodentium. Thus, Clec12a contributes to an innate-immune-surveillance mechanism that controls the expansion of potentially harmful commensals while limiting inflammation. [Display omitted] •The innate immune receptor, Clec12a, regulates colitis severity•Clec12a dictates microbiota composition•In the absence of Clec12a, F. rodentium expands•Clec12a binds F. rodentium and regulates colonization via phagocytosis Chiaro and Greenewood et al. demonstrate that the innate immune receptor, Clec12a, impacts colitis severity by regulating intestinal immune responses to the microbiota. Clec12a controls microbiota composition by binding specific microbiota members, leading to phagocytosis. Clec12a-deficient mice show a heightened inflammatory response, exacerbating colitis that can be transferred via microbiota.