Stress triggers gut dysbiosis via CRF-CRHR1-mitochondria pathway

Psychological stress can lead to gut dysbiosis, yet the precise mechanisms underlying the transfer of stress signals from the brain to the gut remain elusive. Here we describe a new pathway that conveys stress from brain to gut and trigger dysbiosis. Acute stress activates hypothalamic-pituitary-adrenal (HPA) axis and release corticotropin-releasing factor (CRF) to elevate colonocytes’ CRF receptors 1 (CRHR1) expression, which damages mitochondrial ultrastructure and respiration function, as well impairs colon epithelium hypoxia, thereby shifts gut microbiota dominant strains from obligate anaerobes to facultative anaerobes. Blocking CRHR1 or activating mitochondria conferred resilience to stress induced mitochondria damaging and epithelium hypoxia impairing. Furthermore, we corroborated these findings by observing significant changes in serum CRF levels, colonocytes’ mitochondria and gut microbiota in patients with irritable bowel syndrome (IBS). These results suggest that the CRF-CRHR1-mitochondria pathway plays a pivotal role in stress-induced gut dysbiosis that could be therapeutically targeted for stress-induced gastrointestinal diseases.