Stress-induced glucocorticoid signaling impairs enteric neurotrophin BDNF-TrkB pathway and drives gastrointestinal dysmotility.

Stress is a key contributor to gastrointestinal (GI) dysmotility, particularly in patients with disorders of gut-brain interactions. Since GI motility is governed by the enteric nervous system (ENS), stress may act by altering ENS function. While stress activates glucocorticoid signaling via the hypothalamic-pituitary-adrenal axis, the impact of stress-mediated glucocorticoid signaling on ENS biology remains poorly understood. In the central nervous system, glucocorticoids reduce specific isoforms of brain-derived neurotrophic factor (BDNF), impairing signaling through its receptor, tropomyosin related kinase B (TrkB), and contributing to behavioral dysfunction. However, the identity of ENS-specific Bdnf isoforms, their glucocorticoid sensitivity, and the effect of enhanced TrkB signaling on GI motility in stressed animals has not been characterized. Here, using male and female mice, we show that >85% of post-natal ENS Bdnf transcripts are glucocorticoid-responsive isoforms. We also demonstrate that both BDNF and its receptor TrkB (Ntrk2) are expressed by enteric neurons. Stress, in male mice, and administration of dexamethasone (DEXA), a synthetic glucocorticoid receptor agonist, in both male and female mice, cause GI dysmotility, which we demonstrate is associated with significantly reduced Bdnf transcripts in the longitudinal muscle - myenteric plexus tissue in vivo. Dexamethasone exposure also represses Bdnf transcript and mature protein levels in longitudinal muscle - myenteric plexus tissue in vitro. Notably, treatment with HIOC, a selective TrkB agonist, rescues GI transit defects in dexamethasone-treated animals. These findings identify BDNF-TrkB signaling as a key modulator of stress-induced ENS dysfunction and highlight TrkB as a promising therapeutic target for GI dysmotility in disorders of gut-brain interactions.