Beyond energy metabolism: ketogenic diet and β-hydroxybutyrate protect against intestinal ischemia-reperfusion injury through anti-inflammatory and barrier-preserving effects

Intestinal ischemia-reperfusion injury (IRI) is a significant clinical challenge with limited effective treatments. This study investigated the protective effects of ketogenic diet (KD) and β-hydroxybutyrate (BHB) against intestinal IRI using mouse models and intestinal organoids. Following two weeks of KD or BHB administration, mice were subjected to superior mesenteric artery occlusion (60 min) and reperfusion (4 h). Both interventions significantly elevated blood BHB levels and reduced fasting glucose. KD and BHB markedly attenuated intestinal villous damage, preserved epithelial barrier function (E-cadherin, Occludin, ZO-1), maintained mitochondrial integrity, reduced inflammatory cytokines (IL-6, IL-1β, TNF-α), and improved 72-h survival rates, with KD demonstrating superior efficacy. In intestinal organoid oxygen-glucose deprivation models, BHB exhibited differential protective effects at two tested concentrations (2 mM vs. 5 mM), with enhanced protection at the higher concentration on cellular viability, structural integrity, and inflammatory responses. These findings provide the first evidence that ketogenic interventions protect against intestinal IRI through multiple mechanisms including inflammatory suppression and barrier preservation, suggesting potential clinical applications in intestinal IRI prevention and management, though detailed mechanistic elucidation requires further investigation.