Heart-gut axis: Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to prevent cardiovascular disease through gut microbiota

Human gut microbiota (GM) is a unique ecosystem harboring trillions of microbes, is arguably the largest endocrine and paracrine organ in the body. Microbes residing in human intestine produce several bioactive signaling molecules (BSM), which are transported in the systemic circulation to various organs. Development of heart disease or its acceleration is seen in individuals who have coexisting gastrointestinal disorders. Dysbiosed GM (altered gut microbial composition) produce high levels of harmful BSM such as trimethylamine (TMA)/trimethylamine-N-oxide (TMAO), bile acids (BAs), uremic toxins, lipopolysaccharide (LPS), low concentrations of short chain fatty acids (SCFAs). Intestinal epithelial cells (IECs) in dysbiosed gut synthesize reduced levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), the key regulator of LDL-C clearance. The expression of PCSK9 in IECs depends on the host metabolic status and dietary habits. Decreased production of PCSK9 in the gut may promote imbalance in cholesterol metabolism leading to atherosclerotic cardiovascular disease (ASCVD). In contrast, in the normal gut the optimum production of PCSK9 show a protective effect on the cardiovascular system by regulating low-density lipoprotein receptor (LDLR) expression and apolipoprotein-B-lipoprotein cholesterol biosynthesis. However, a definitive link between the intestine-derived PCSK9 in cholesterol homeostasis and cardiovascular risk remains poorly understood. The objective of this review is to present the current knowledge and discuss the heart-gut-PCSK9 interaction, for a better understanding of the role GM in the regulation of cholesterol metabolism. We have presented the available evidences implicating a bidirectional cross-talk between heart and gut in reducing LDL-C through PCSK9, and also highlighted the prospects of GM-targeted treatment strategies for ASCVD prevention. Proposed mechanism of gut-heart interaction. GM produce beneficial as well as deleterious effects in heart due to the production of useful and harmful metabolites. Dysbiosed GM produce high levels of harmful metabolites like TMAO, BAs, Uremic toxins and LPS, and reduced levels of SCFAs (e.g. butyrates), which induce atherosclerosis. In dysbiosed gut, decreased production of PCSK9 by IECs cause imbalance in intestinal cholesterol metabolism. However, in normal gut, the optimum production of SCFAs and PCSK9 elicit protective effects on cardiovascular system by promoting cholesterol homostasi