Irritable bowel syndrome (#IBS ) is characterized by chronic abdominal pain and altered bowel habits, with visceral hypersensitivity and impaired intestinal barrier function as key pathophysiological features. Although peripheral determinants of barrier dysfunction have been studied, the contribution of central regulatory mechanisms remains unclear. β-Hydroxybutyrate (#BHB ), a major ketone body elevated during fasting, exhibits anti-inflammatory and barrier-protective effects peripherally, but its central actions are unknown. Here, we investigated whether BHB acts within the brain to regulate intestinal barrier function and visceral sensitivity using an LPS-induced rat model. Intracisternal BHB dose-dependently attenuated LPS-induced colonic hyperpermeability and visceral hypersensitivity, whereas an equivalent subcutaneous dose was ineffective, indicating a centrally mediated effect. The protection conferred by intracisternal BHB was abolished by vagotomy and by pharmacological inhibition of brain AMPK, orexin 1 receptors, histamine H1 receptors, basal forebrain cholinergic neurons (BFCNs), or adenosine A2B receptors. Peripheral BHB also ameliorated barrier dysfunction and visceral hypersensitivity; however, these effects persisted after vagotomy while remaining sensitive to central pharmacological blockade, suggesting engagement of shared brain signaling modules together with vagus-nonobligatory components. Collectively, these findings demonstrate that BHB regulates intestinal barrier function and visceral sensitivity through both central and peripheral mechanisms. Central BHB signaling engages an AMPK-orexin pathway involving histamine H1 receptors, BFCNs, adenosine A2B receptor-related mechanisms, and vagal pathways. BHB thus emerges as a neuro-metabolic signal modulating core gut-brain interaction processes and represents a promising therapeutic target for leaky gut-associated disorders, particularly IBS.
https://www.sciencedirect.com/science/article/abs/pii/S0006295226002790
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