Most of us have experienced at first hand the effects of stress on our digestive systems. As early as 1833, Beaumont (1) described that fear and anger influenced acid secretion from the stomach of his patient Alexis St. Martin, a Canadian trapper with a permanent gastric fistula caused by a gunshot wound. The impact of psychological, physical, and immunological stressors on gastrointestinal secretion, motility, epithelial permeability, and inflammation is now thoroughly documented, and stress has a major influence on digestive diseases (refs. 2–4 and references therein). Most studies concern central mechanisms whereby a stressful event perceived by the brain triggers neuronal and hormonal reflexes that influence the gut. However, a report by la Fleur et al . in this issue of PNAS (5) makes the exciting observation that the intestine produces the same stress peptides that are present in the central nervous system. A local stressor, in this case a bacterial toxin that is the principal cause of antibiotic-induced colitis and diarrhea, results in the local generation and action of stress peptides that mediate inflammation without involving the central nervous system (Fig. 1). These peptides also regulate the transit of digested material through the intestine under normal conditions. This intrinsic stress response mechanism may mediate altered digestive processes that accompany physical and chemical insults to the intestine and could contribute to poorly understood disorders, such as inflammatory bowel disease and irritable bowel syndrome, for which stress exacerbates the symptoms. Fig. 1. Stress-induced alterations in gastrointestinal functions. Central stressors induce release of CRF, ACTH, and glucocorticoids, which have antiinflammatory actions. Centrally released CRF and Ucns activate parasympathetic nerves, which in turn innervates enteric neurons within the gut wall to stimulate or inhibit motility (depending on the region) and stimulate secretion. Peripheral stressors induce local release of CRF and Ucns, possibly from …