Depression represents a typical mental condition, yet whether intestinal metabolic signals drive central neural circuits remains unclear. Here we identify ileal enteric neuronal Gpbar1 as a previously unrecognized peripheral node that coordinates gut-to-brain communication to prevent depression-like behavior through a vagus-dependent, nucleus tractus solitaries (NTS)-paraventricular nucleus (PVN) signaling axis. The enteric plexus Gpbar1 is predominantly expressed on a subpopulation of GAD1-positive GABAergic neurons. Chronic restraint stress suppresses Gpbar1 expression, triggers glycolytic reprogramming and mitochondrial distress in both ileum and hypothalamus. Oral Gpbar1 agonism with INT-777 reverses hypothalamic HK2/TOM20 alterations and behavioral abnormalities by enhanced ileal mTOR/HIF-1 alpah signaling and glycolysis-related metabolite shifts, an effect specifically abolished by subdiaphragmatic vagotomy or chemogenetic silencing of PVN GABAergic neurons. Our findings establish ileal Gpbar1 as a gut-derived metabolic sensor that engages a defined vagal-brainstem-hypothalamic inhibitory circuit to regulate depressive phenotypes, shifting the roadmap from brain-centered to gut-initiated antidepressant mechanisms and unveiling a compelling peripheral therapeutic strategy that bypasses intractable central brain-directed intervention.
Zhong, L., Shu, Y., Yan, M., Wang, L., Wu, M., Wu, J., Yang, S., Gu, Z., Chen, Z., Xin, G., Guan, S., Tian, T.
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