β-Hydroxybutyrate Modulates Intestinal Barrier and Visceral Sensitivity via Brain AMPK-Orexin Pathway in Rats

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits. Key pathophysiological features include visceral hypersensitivity and impaired intestinal barrier function, often referred to as 'leaky gut'. While peripheral factors contributing to barrier dysfunction are well-studied, the precise contribution of central regulatory mechanisms remains largely unclear. β-Hydroxybutyrate (BHB), a primary ketone body elevated during fasting, is known for its anti-inflammatory and barrier-protective effects in peripheral tissues. However, its potential central actions in modulating gut-brain interactions, particularly in the context of IBS-like symptoms, have not been elucidated, representing a critical gap in understanding neuro-metabolic regulation of gut health.

Researchers investigated the central and peripheral effects of β-Hydroxybutyrate (BHB) on intestinal barrier function and visceral sensitivity using an LPS-induced rat model. Rats received either intracisternal or subcutaneous administration of BHB at various doses (dose-dependently). Control groups received LPS without BHB. To dissect the underlying mechanisms, specific interventions included vagotomy and pharmacological inhibition of key brain pathways: AMPK, orexin 1 receptors, histamine H1 receptors, basal forebrain cholinergic neurons (BFCNs), and adenosine A2B receptors. Primary endpoints measured were colonic hyperpermeability and visceral hypersensitivity, assessed using standard physiological and behavioral assays.

Intracisternal BHB dose-dependently attenuated LPS-induced colonic hyperpermeability and visceral hypersensitivity, demonstrating a clear centrally mediated effect, as an equivalent subcutaneous dose was ineffective. The protective effects of central BHB were completely abolished by vagotomy, highlighting the critical role of vagal output. Pharmacological inhibition of brain AMPK or orexin 1 receptors also eliminated the benefits of intracisternal BHB, indicating their essential involvement in the central signaling pathway. Further, the study found that histamine H1 receptors, BFCNs, and adenosine A2B receptors were all crucial for the central BHB-mediated protection. Peripheral BHB also ameliorated barrier dysfunction and visceral hypersensitivity; however, these effects persisted after vagotomy, suggesting engagement of shared brain signaling modules but also vagus-nonobligatory components.

Central BHB signaling engages an AMPK-orexin pathway involving histamine H1 receptors, BFCNs, adenosine A2B receptor-related mechanisms, and vagal pathways to modulate gut function.