Ketogenic Diet Alleviates Hypoglycemia‐Induced Neuroinflammation via Modulation the Gut Microbiota in Mice

Scope This study aims to investigate the role of gut microbiota regulation with ketogenic diet (KD) in hypoglycemia‐induced neuroinflammation. Methods and results Immunofluorescence staining and western blotting show that KD alleviates blood‐brain barrier injury induced by hypoglycemia by increasing Podxl and zonula occludens‐1 (ZO‐1) levels. KD‐fed mice show reduced brain edema by decreasing aquaporin‐4 (AQP4) content and maintaining its polarized expression. 16S rRNA gene amplicon sequencing results show that KD reduces the Chao 1 index of gut microbiota α‐diversity, and significant separation is detected in the β‐diversity analysis between the control and KD‐fed mice. KD increases the relative abundance of Firmicutes and Proteobacteria and decreases that of Bacteroidetes . Hypoglycemia can reduce SOD and GSH‐PX levels while increasing TNF‐α, IL‐1β, and IL‐6 mRNA levels in the brain tissues of mice. KD alleviates hypoglycemia‐induced neuroinflammation by inhibiting microglia activation and TLR4/p38MAPK/NF‐κB signaling pathway. Importantly, antibiotic cocktail depletion of the gut microbiota weakens anti‐inflammatory and antioxidation responses in KD‐fed mice. Conclusion Collectively, these findings suggest that KD alleviates hypoglycemia‐induced brain injury via gut microbiota modulation, which may provide novel insights into the therapy for hypoglycemia.