Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na⁺ channel formed by claudin-2. Relative to wild-type, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2-deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance.

腹泻是宿主对肠道病原体的反应，但其对发病机理的影响尚不清楚。通过用附着和消灭的细菌柠檬酸杆菌感染小鼠，我们确定了腹泻和肠屏障丧失对宿主防御的机制和作用。感染后2天内发生通透性增加，并与上皮紧密连接蛋白claudin-2的IL-22依赖性上调相吻合。渗透率的增加仅限于小分子，这是claudin-2形成的细胞旁水和Na ⁺通道所期望的。相对于野生型，claudin-2缺陷型小鼠，他们经历了严重的疾病，包括啮齿类念珠菌的粘膜定居增加，病原体延长脱落，细胞因子反应过度和更大的组织损伤。相反，转基因claudin-2的过表达降低了疾病的严重程度。化学诱导的渗透性腹泻降低了claudin-2缺陷小鼠（但不是转基因小鼠）的结肠炎严重性和啮齿类念珠菌的负担，表明claudin-2介导的保护作用是水流出增强的结果。因此，IL-22诱导的claudin-2上调驱动腹泻和病原体清除。