Gut Parabacteroides merdae protects against cardiovascular damage by increasing commensal bacteria-driven branched-chain amino acid catabolism

Abstract

Atherosclerosis is a chronic inflammatory disease of arteries featured with accumulated lipids, becoming the primary cause of cardiovascular diseases and death. Branched-chain amino acids (BCAAs) accumulation is defined as biomarkers of cardiometabolic diseases. Here, we revealed metabolic benefits of a previously reported gut microbiota-modulator (GMD) on atherosclerosis in ApoE −/− mice, and identify a gut symbiont Parabacteroides merdae -driven BCAA catabolism beneficial for the alleviation of atherosclerosis lesions. We also show that the porA gene responsible for the conversion of BCAAs into branched short-chain fatty acids is required for the in vivo efficacy of P. merdae. Furthermore, the down-regulation of BCAA-activated plaque mammalian target of rapamycin complex 1 (mTORC1) pathway is suggested as the mechanism underlying the benefits of P. merdae . Our results demonstrate the critical role of the commensal bacteria-driven BCAA catabolism in maintaining the host cardiovascular health and supporting the gut microbiota-targeted therapeutic strategy for cardiometabolic diseases.