Our study is the first to show that S100B, which is increased during CDI in humans and mice, is an important regulator of inflammatory response during CDI, thereby functioning as a key mediator of the intestinal tissue injury and diarrhea by upregulating a variety of proinflammatory mediators (IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2) and downregulating protective mediators (SOCS2, IL-22, and Bcl-2). Here, TNF is linked to clostridium difficile infection.