A Two-Component System Regulates Bacteroides fragilis Toxin to Maintain Intestinal Homeostasis and Prevent Lethal Disease

Intestinal microbes are recognized for their role in human disease. Enterotoxigenic Bacteroides fragilis (ETBF) has been implicated in inflammatory bowel disease and colorectal cancer; however, colonization alone is insufficient to cause these illnesses. We hypothesized that homeostasis in healthy carriers is maintained by colonic mucus, the major constituent of which is the glycoprotein Muc2. We found that Muc2-deficient mice succumb to lethal disease from ETBF colonization in a B. fragilis toxin (BFT)-dependent manner. We identify a toxin regulator, the two-component system RprXY, which suppresses BFT expression in vitro and in vivo. Overexpression of either component was sufficient to prevent lethal disease in Muc2-deficient mice. Our studies demonstrate that homeostasis in the context of ETBF colonization is dependent on a dynamic interaction between intestinal mucus, a bacterial toxin, and a toxin regulatory system. Regulation of virulence may offer a therapeutic target to maintain intestinal homeostasis in susceptible patients. Enterotoxigenic B. fragilis is associated with inflammatory disease of the colon. Hecht, Casterline, and colleagues report that mucus-deficient mice are susceptible to lethal colitis. Suppressing toxin expression by manipulating a bacterial two-component system restores homeostasis, linking the host environment to pathogen virulence and providing a strategy to modify disease outcome.