Blautia coccoides-derived metabolite trimethylamine-N-oxide exacerbates Alzheimer's disease progression via targeting HIF1α signaling.

An increasing number of studies have shown that commensal gut microbes may be involved in the pathogenesis of Alzheimer's disease (AD). The influence of gut microbe-derived metabolites, such as trimethylamine N-oxide (TMAO), has attracted a lot of attention. However, the influence and pathways mediated by gut microbe-derived metabolites in the pathogenesis of AD remain uncertain. Here, we observed a significant increase in the abundance of Blautia coccoides in AD patients, which showed positive predictive value for serum p-Tau181 levels. Supplementation with B. coccoides could exacerbate cognitive impairment and Tau phosphorylation in P301s mice. We identified TMAO as a key B. coccoides-derived metabolite promoting Tau phosphorylation by functional gene analysis, metabolomic analysis and VIP analysis, and further demonstrated that it was able to promote oxidative stress of AD in vitro. Mechanistically, TMAO could bind to hypoxia-inducible factor 1 alpha (HIF1α) at 235-238 sites, which promoted oxidative stress through the inhibition of HIF1α signal, thereby aggravating AD pathology. This study elucidated the important role of B. coccoides-derived metabolite TMAO in exacerbating AD and provided new insights for gut microbe/metabolite-based therapeutic strategies.