Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Loss 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 of Enterococcus faecium ( Efm ) from the gut microbiota. Efm inoculation 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, Efm was unable to protect mice carrying a NOD2 gene 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. ### Competing Interest Statement K.C. has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech, and Abbvie. K.C. has consulted for or received an honoraria from Puretech Health, Genentech, and Abbvie. K.C. is an inventor on U.S. patent 10,722,600 and provisional patent 62/935,035 and 63/157,225. H.C.H. has received research support from Rise Therapeutics and LISCure Biosciences. U.S. patents PCT/US16/28836 (H.C.H.) and PCT/US2020/019038 (H.C.H. and M.E.G.) were obtained for the commercial use of SagA-engineered bacteria. Rise Therapeutics has licensed these patents to develop SagA-probiotics as therapeutics. J.A. reports consultancy fees, honoraria, or advisory board fees from Abbvie, Adiso, Bristol Myers Squibb, Janssen, Pfizer, Fresnius, and BioFire Diagnostics.