Yak milk ameliorates chronic alcohol-induced brain injury in mice by modulating the gut microbiota and suppressing the TLR4/NF-κB pathway

This study investigated the protective effects of yak milk (YM) on chronic alcohol-related brain injury (ARBI) in mice. The findings revealed that YM intake significantly alleviated alcohol-induced anxiety-like behaviors, and offered protection against ARBI by decreasing oxidative stress and suppressing the inflammatory response in the brain tissues. Notably, the effects were more pronounced in the high-dose yak milk (HY) group compared to the low-dose yak milk (LY) and high-dose regular cow's milk (HM) groups. Additionally, YM was found to influence the gut microbiota in mice, particularly in relation to microorganisms associated with neuroinflammation and depressive behaviors, such as <i>Parabacteroides</i> and <i>Alistipes</i>. Metabolite analysis revealed that the levels of linoleic acid, <i>N</i>-arachidonoyl dopamine, norlobaridone, epothilone A, xanthotoxol, and indoprofen were significantly elevated in the HY group. Furthermore, KEGG analysis suggested that YM intervention primarily affected the pathways of ABC transporters, cysteine and methionine metabolism. Subsequently, western blot analysis confirmed that this intervention inhibited TLR4 and NF-κB p65 protein levels, leading to a reduction in inflammatory expression. Therefore, we propose that YM provides protection against ARBI and anxiety-like behaviors in mice by modulating oxidative stress, influencing the expression of inflammatory mediators associated with the TLR4/NF-κB pathway, and regulating the gut microbiota and metabolic processes through the "gut-brain" axis.