Butyrate alleviates cognitive impairment by improving gut mucosal barrier function and blocking neuroinflammatory signaling in LDLR-/- mice

Abstract Background Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fiber, possess neuroactive properties. The present study aimed to explore whether SCFAs-butyrate can repress neuroinflammation and alleviate cognitive impairment via improving gut mucosal barrier function and mediating tryptophan metabolism in LDLR −/− mice. Methods LDLR −/− mice were fed an atherosclerotic diet with 1.25% cholesterol and 40% calories from fat and concomitantly treated by intragastric administration with either normal saline as model group or 400mg/kg/day sodium butyrate for 8 weeks. Results For gut barrier function, butyrate increased expression of tight junction protein, and inhibited intestinal inflammatory pathways by targeting the toll-like receptor 4 signaling and the nod-like receptors domain containing 3 (NLRP3) inflammasome. Subsequently, butyrate reduced not only the serum lipopolysaccharide level but also its capability to cross the blood-brain barrier, leading to the suppression of tau phosphorylation and the improvement of neuroinflammation by inhibiting the increase in reactive microglia and astrocytes, and blocking NLRP3 inflammasome activation in the cortex and hippocampus. Final behavioral tests indicated that butyrate delayed cognitive impairment via decreasing latency to the platform and lengthening swimming distance in the target quadrant. Nevertheless, butyrate showed no effect on serotonin, indoleacetic acid, L-kynurenine, niacinamide, and their metabolites, indicating that the observed effects on cognitive function are unrelated to the tryptophan metabolism. Conclusion In summary, the present study provided the novel experimental evidence that butyrate played a neuroprotective role by targeting the NLRP3 inflammasome. The reduction of neuroinflammation may be related to the improvement of gut mucosal barrier function and the decrease of the penetration of intestinal endotoxin from the gut to the central nervous system.