Ticagrelor combined with aspirin displays the signature of regulating the gut microbiome in consistence with improving the immuno-inflammatory response in atherosclerosis

The gut microbiome shape the host immune system and influence the outcomes of various cardiovascular disorders, meanwhile, it is a malleable microbial community that can be remodeled in response to various factors, including medications. Experiment implicated ticagrelor, one of the P2Y12 inhibitors, exerted antibacterial activity against gram-positive bacteria established from clinical evidence that it could reduce the incidence of infection-related disease. Here we performed 16S rRNA and metagenomic analysis from patients with unstable angina pectoris (UAP) treated with ticagrelor plus aspirin or clopidogrel plus aspirin for one month to determine the composition and functions of the gut microbiome difference between the two main medications. Our results suggested that the functional peptidoglycan (PGN) and Staphylococcus aureus (S. aureus) infection biosynthesis pathways were downregulated with ticagrelor-aspirin treatment in the gut. Furthermore, we found these changes were accompanied by increasing peripheral regulatory T cells (Tregs) and ectonucleotidases CD39/CD73 expressions with responding to ameliorating inflammation. To further validate the result, 16S rRNA and metabolomic analysis were carried out upon Western-diet (WD)-fed ApoE-/- mice, we found mice treated with ticagrelor plus aspirin exerted optimal synergistic effects on reducing the plaque burden and ameliorating inflammation through altered composition and functions of the gut microbiome which keeping in line with our clinical findings. The current study, for the first time, demonstrated the athero-protective effect of ticagrelor and displayed its therapeutic value at least partially attributed to its manipulation of gut microbiota. Graphic abstract Ticagrelor acts on intestinal bacteria after oral administration, reducing several pathogenic Gram-positive (G+) bacteria at phyla Firmicutes and the Firmicutes/Bacteroidetes (F/B) Ratio, thus decreasing the gut peptidoglycan (PGN) synthesis. The reduction of the above pathogenic factors causes the polarization of peripheral T lymphocytes toward Treg cells. The elevated Treg cells are accompanied by an increased expression of CD39/CD73 on Tregs, which hydrolyze the extracellular ATP generated from damaged endothelial cells into adenosine (ADO) with anti-inflammatory properties and ultimately inhibited the inflammation of atherosclerosis (AS).