HMGB1 functions as a critical mediator of host defense at the gut mucosal barrier.

Host cells and bacteria constantly communicate across the gut mucosal barrier, yet the molecular details of these interactions remain largely unknown. Here, we report a molecular feedback loop between high mobility group box 1 (HMGB1) and bacteria that express an evolutionarily conserved amino acid sequence, target of HMGB1 (ToH1). HMGB1 is released into the colonic mucus in response to the microbiota, where it binds to ToH1-containing proteins on the bacterial surface. This binding promotes bacterial aggregation, limits mucosal invasion, and blocks adhesion to host tissues. Commensal bacteria that encounter HMGB1 subsequently downregulate expression of ToH1-bearing adhesins. In ulcerative colitis, HMGB1 defense is compromised, and low HMGB1 levels associate with enrichment of ToH1-positive adherent bacteria. ToH1 is broadly utilized, critical for virulence, and differentially expressed between commensal and pathogenic states. These characteristics suggest that ToH1 functions as a microbial virulence determinant and may serve as a target for developing antibacterial strategies that precisely target virulent bacteria.