Antimicrobial overproduction sustains intestinal inflammation by inhibitingEnterococcuscolonization

Abstract

SUMMARYLoss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion ofEnterococcus faecium(Efm) from the gut microbiota.Efminoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1β secretion and increased the proportion of IL-22-producing CD4+T helper cells and innate lymphoid cells. Finally,Efmwas unable to protect mice carrying aNOD2gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.