Gut Commensal Bacteroides thetaiotaomicron Promote Atherothrombosis via Regulating L-Tryptophan Metabolism

Abstract

Background: Coronary thrombosis events continue to be the leading cause of morbidity and mortality worldwide. Recently, emerging evidence has highlighted the role of gut microbiota in cardiovascular disease, but few studies have systematically investigated the gut microbiota variation associated with atherothrombosis. Methods: We conducted multi-omics analysis (metagenomics sequencing and serum metabolomics) on 146 subjects from Peking Union Medical College Hospital-Coronary Artery Disease (PUMCH-CAD) cohort. We analyzed the key strains and metabolic pathways related to coronary artery disease (CAD) development, explored the bacterial functional pathway which contributes to atherothrombosis at strain level in depth. Single strain colonization procedures on germ free mice demonstrated the promotion of platelet activation and thrombotic phenotypes of the disordered gut microbiota. Results: Gut microbiome and serum metabolome shifts were apparent in cases of CAD progression, Bacteroides spp. disturbed the development of CAD by participating in lipopolysaccharide (LPS), menaquinone and methanogenesis pathways. Particularly, coronary thrombosis is characterized by increased circulatory levels of L-tryptophan, which correlate with Bacteroides thetaiotaomicron that has enriched biosynthetic potential. In germ free mice we demonstrate that Bacteroides thetaiotaomicron colonization could induce thrombosis, aggravate platelet hyperreactivity and augment fecal levels of L-tryptophan. Conclusions: The disordered gut microbiota of CAD contributed to the occurrence and development of atherothrombosis. The key members of the bacterial and metabolic features may become biomarkers for predicting the cardiovascular thrombosis event. Targeting the microbial pathway may have the potential to reduce the incidence of cardiovascular disorders. Clinical Trial Registration: ChiCTR2000033897, https://www.chictr.org.cn/showproj.html?proj=55023.

Keywords

• gut microbiota
• coronary artery disease
• myocardial infarction
• atherothrombosis
• bacteroides thetaiotaomicron
• l-tryptophan