The gut microbiota is altered in Alzheimer’s disease (AD) patients and may contribute to AD by secreting microbial metabolic product that affect immunologic and/or neuronal function. Western diet is linked to increased AD risk and has differential effects on the gut microbiota. Whether the Western diet affects AD pathogenesis via modulating microbiota metabolic function has not been extensively investigated in mechanistic animal models. We hypothesize that the Western high-fat high-sugar diet worsens AD by shifting gut microbiota metabolites. In the male APP/PS1 mice, we first identified increased amyloid plaque burden in the hippocampal region and increased CD4+IFNγ+ and CD4+T-bet+ splenic cell populations in Western-diet-fed mice (vs control-diet-fed AD male mice). Further, we identified IL1B signaling as a central upregulated node in microglia gene expression and Ingenuity Pathway Analysis, with predicted upstream contributions from upregulated ITGAV, AGT, INSR and downregulated NFAT5. Collectively, these findings indicated that Western diet has a sex-dependent effect and exacerbate amyloid pathology and promotes systemic Th1 immune activation and microglial IL-1b-centered innate inflammatory priming in APP/PS1 male mice. Next, we identified strict anaerobes Muribaculaceae and Rikenellaceae RC9 gut group increased by Western diet vs Control diet. Interestingly, we correlated the microbiota with plaque burden in the brain and identified butyrate-produces including Lachnospiraceae, Butyricicoccus, Ruminococcaceae, Oscillospiraceae, and Rosburia were negatively related with plaque levels in the western diet group.
Our findings implicate Western diet–driven bacterial metabolites in exacerbated inflammation in APP/PS1 male mice, and we aim to link diet-induced gut microbiota to host metabolic and inflammatory responses using multi-compartment metabolomic analyses. We are  further working on the cecal, serum and cortical metabolomic data to identify host metabolic alterations attributed to the temporal alterations of gut microbiota.