Abstract

Ulcerative colitis (UC) is characterized by intestinal inflammation, barrier dysfunction, and dysbiosis, with limited treatment options. Here, we demonstrate that Lactobacillus delbrueckii is commonly reduced in low-birth-weight piglets, dextran sulfate sodium (DSS)-induced colitis mice, and UC patients. L. delbrueckii and its surface proteins mitigate intestinal inflammation in a macrophage-dependent manner. We further identify P4430, a DUF4430-domain-containing protein, as a key surface protein that protects against intestinal inflammation by suppressing M1 polarization and downregulating inflammatory responses of macrophages. Mechanistically, P4430 reduces inflammation by binding to and inhibiting Mincle, a C-type lectin receptor. These findings elucidate a key effector molecule of L. delbrueckii in modulating inflammatory responses and highlight the therapeutic potential of commensal bacteria and their cellular components in treating UC and possibly other intestinal inflammatory diseases.