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得到认可。产肠毒素脆弱拟杆菌(ETBF) 与炎症性肠病和结直肠癌有关；然而，仅殖民化不足以引起这些疾病。我们假设健康携带者的体内平衡是由结肠粘液维持的，其主要成分是糖蛋白 Muc2。我们发现 Muc2 缺陷小鼠会以脆弱拟杆菌毒素 (BFT) 依赖性方式因 ETBF 定植而死于致命疾病。我们确定了一种毒素调节剂，即双组分系统 RprXY，它可以在体外和体内抑制 BFT 表达。任何一种成分的过度表达都足以预防 Muc2 缺陷小鼠的致命疾病。我们的研究表明，ETBF 定植背景下的体内平衡取决于肠道粘液、细菌毒素和毒素调节系统之间的动态相互作用。毒力调节可能为易感患者维持肠道稳态提供治疗靶点。