Aspirin ameliorates atherosclerotic immuno-inflammation through regulating the Treg/Th17 axis and CD39-CD73 adenosine signaling via remodeling the gut microbiota in ApoE-/- mice

The gut microbiome has been implicated in the development of cardiovascular disease (CVD) and atherosclerosis (AS), a chronic inflammatory condition. Aspirin may improve the immuno-inflammatory status in AS by regulating microbiota dysbiosis. However, the potential role of aspirin in modulating gut microbiota and microbial-derived metabolites remains less explored. In this study, we investigated the effect of aspirin treatment on AS progression by modulating gut microbiota and microbial-derived metabolites in apolipoprotein E-deficient (ApoE^-/-) mice. We analyzed the fecal bacterial microbiome and targeted metabolites, including short-chain fatty acids (SCFAs) and bile acids (BAs). The immuno-inflammatory status of AS was evaluated by analyzing regulatory T cells (Tregs), Th17 cells, and the CD39-CD73 adenosine signaling pathway involved in purinergic signaling. Our results indicated that aspirin altered gut microbiota, leading to an increase in the phylum Bacteroidetes and a decrease in the Firmicutes to Bacteriodetes (F/B) ratio. Aspirin treatment also increased levels of targeted SCFA metabolites, such as propionic acid, valeric acid, isovaleric acid, and isobutyric acid. Furthermore, aspirin impacted BAs by reducing the level of harmful deoxycholic acid (DCA) and increasing the levels of beneficial isoalloLCA and isoLCA. These changes were accompanied by a rebalancing of the ratio of Tregs to Th17 cells and an increase in the expression of ectonucleotidases CD39 and CD73, thereby ameliorating inflammation. These findings suggest that aspirin has an athero-protective effect with an improved immuno-inflammatory profile, partially attributed to its manipulation of the gut microbiota.