CRH, the hypothalamic component of the HPA axis, attenuates inflammation through stimulation of glucocorticoid release, while peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and upregulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid (TNBS) induced-experimental colitis we demonstrate that, despite low glucocorticoid levels, CRH deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis, and possibly in inflammatory bowel disease in humans. Moreover, they suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.