Targeting enteric glial CRF-R1/Cx43 attenuates stress-induced accelerated colonic motility

Abstract

Stress triggers disorders in accelerated peristalsis, with corticotropin releasing factor receptor 1 (CRF-R1) playing a pivotal role. Enteric glia cells (EGCs) and glial Cx43 are known to influence gastrointestinal motility, yet their involvement in colonic motor responses to stress remains unclear. Using immunofluorescence and single-cell RNA sequencing data, we identified CRF-R1 expression in EGCs. Male C57BL/6 mice subjected to wrap restraint stress (WRS) revealed stress-induced colonic motility changes. By employing Fluoroacetate, NBI 27914, and Gap26, we elucidated the impact of glial CRF-R1/Cx43 on stress-induced colonic motor responses. Our study demonstrated CRF-R1 expression in EGCs of the small intestine and colon, along with elevated CRF levels and upregulated CRF-R1 in the distal colon under stress. Antagonizing CRF-R1 and disrupting EGC function made mice resistant to colonic stress responses. Mechanistically, increased glial Cx43 expression and activity influenced colonic motor responses in a CRF-R1-dependent manner. Our findings highlight the role of EGC-derived CRF-R1 in stress-induced colonic motor responses via Cx43 activation. Targeting CRF-R1/Cx43 signaling in EGCs may offer a promising approach to mitigate stress-induced colonic transit changes.