Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder in which loss of intrinsic enteric neurons (iENs) has been documented. However, the contribution of gut microbiota to the loss of iENs in IBD remains poorly defined. Here, we identify an IBD-enriched intestinal pathogen, Clostridium symbiosum (C. symbiosum) , which exacerbates iEN loss and colitis. Mechanistically, C. symbiosum -derived succinate, emerging as a central mediator, drives macrophage glycolysis via the H3K79succ/HK2 axis, thereby sustaining IL-1β secretion, which, in turn, promotes neuronal-specific NLRP3 inflammasome activation and consequent neuronal loss. We further demonstrated that preventing iEN loss effectively improves outcomes in C. symbiosum -exacerbated colitis. Importantly, we identified phiCS-1, an endolysin from C. symbiosum -specific bacteriophages, which efficiently lyses C. symbiosum and markedly attenuates C. symbiosum -mediated iEN loss and colitis. Together, our study provides insights into the intricate interplay between gut microbiota and immune-neuron crosstalk, offering avenues for targeted therapeutic interventions in IBD.