Chronic psychosocial stress induces reversible mitochondrial damage and corticotropin-releasing factor receptor type-1 upregulation in the rat intestine and IBS-like gut dysfunction

The association between psychological and environmental stress with functional gastrointestinal disorders, especially irritable bowel syndrome (IBS), is well established. However, the underlying pathogenic mechanisms remain unknown. We aimed to probe chronic psychosocial stress as a primary inducer of intestinal dysfunction and investigate corticotropin-releasing factor (CRF) signaling and mitochondrial damage as key contributors to the stress-mediated effects. Wistar-Kyoto rats were submitted to crowding stress (CS; 8 rats/cage) or sham-crowding stress (SC; 2 rats/cage) for up to 15 consecutive days. Hypothalamic-pituitary-adrenal (HPA) axis activity was evaluated. Intestinal tissues were obtained 1 h, 1, 7, or 30 days after stress exposure, to assess neutrophil infiltration, epithelial ion transport, mitochondrial function, and CRF receptors expression. Colonic response to CRF (10 μg/kg i.p.) and hyperalgesia were evaluated after ending stress exposure. Chronic psychosocial stress activated HPA axis and induced reversible intestinal mucosal inflammation. Epithelial permeability and conductance were increased in CS rats, effect that lasted for up to 7 days after stress cessation. Visceral hypersensitivity persisted for up to 30 days post stress. Abnormal colonic response to exogenous CRF lasted for up to 7 days after stress. Mitochondrial activity was disturbed throughout the intestine, although mitochondrial response to CRF was preserved. Colonic expression of CRF receptor type-1 was increased in CS rats, and negatively correlated with body weight gain. In conclusion, chronic psychosocial stress triggers reversible inflammation, persistent epithelial dysfunction, and colonic hyperalgesia. These findings support crowding stress as a suitable animal model to unravel the complex pathophysiology underlying to common human intestinal stress-related disorders, such as IBS.