Sodium butyrate alleviates chronic alcoholic neuroinflammation by regulating microgila polarization through GPR109A / PPAR-γ / NF-κB signaling pathway

Abstract Background Alcohol can cause neuroinflammation, leading to neuron damage and further memory and cognitive impairment. Recent animal studies have shown that the exposure to chronic alcohol consumption induces robust inflammatory microglial activation in the brain. However, as a novel anti-inflammation approach, the impact of sodium butyrate on chronic alcohol-induced neuroinflammation still remains unclear. Methods Sixty female C57BL/6J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. Mice were subjected to different behavioral tests to assess aberrant behaviours (deficits in cognitive functions, depression and anxiety). Pathological changes were further investigated by Hematoxylin and eosin staining (HE) and Nissl staining. The microglial activation and microglial polarization were observed by immunohistochemistry (IHC), immunofluorescence (IF) and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of inflammatory factors. G-protein coupled receptor 109A (GPR109A), peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) mRNA and protein levels were evaluated by reverse transcription‑quantitative (RT‑q) PCR and western blot (WB). Results As indicated by the behavioural tests, inflammatory indicators, microglial activation (M1/M2 microglia polarization) and brain morphology, sodium butyrate administration ameliorated aberrant behaviours (locomotor hypoactivity, anxiety disorders and depressive behaviours, impaired learning and spatial recognition memory), effectively reduced neuroinflammation and neuronal damage. The effectiveness of sodium butyrate may attribute to the GPR109A receptor in microglia by up-regulating the expression of PPAR-γ and inhibiting the activation of NF-κB. Conclusion Sodium butyrate ameliorates neuroinflammation induced by chronic alcohol exposure and improves memory and cognitive functions in mice via modulating microglia-mediated GPR109A / PPAR-γ / NF-κB signaling pathway.