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.

肠道微生物因其在人类疾病中的作用而闻名。脆弱的肠毒素细菌（ETBF）与炎症性肠病和大肠癌有关；但是，仅靠殖民地就不足以引起这些疾病。我们假设健康携带者体内的稳态由结肠黏液维持，结肠黏液的主要成分是糖蛋白Muc2。我们发现，Muc2缺陷型小鼠以脆弱的芽孢杆菌毒素（BFT）依赖性方式从ETBF定植中死于致死性疾病。我们确定了一种毒素调节剂，两组分系统RprXY，在体外和体内抑制BFT表达。任一成分的过表达都足以预防Muc2缺陷小鼠的致死性疾病。我们的研究表明，在ETBF定植的背景下，体内稳态取决于肠道粘液，细菌毒素和毒素调节系统之间的动态相互作用。毒力的调节可能为维持易感患者的肠道稳态提供治疗靶点。