Does the Human Gut Microbiome Serve as a Novel Personalized Therapeutic Target for Coronary Atherosclerosis?

Introduction:

The human gastrointestinal system is populated with a variety of symbiotic microorganisms, namely microbiota. Its total weight is approximately 2 kilograms, containing trillions of microorganisms. The microbiome is the total genetic (metagenomic) data of the microbiota. In recent years, the development of efficient methods for genome sequencing and bio-informatics has enabled fast and accurate quantification and qualification of the microbiome, made microbiome analysis leading method of microbiota research.

Coronary artery disease (CAD) accounted for more than 8 million deaths yearly worldwide. In particular, acute coronary syndrome (ACS) remains a major cause of morbidity and mortality and is responsible for more than 1 million hospital admissions in the United States annually. The pathophysiologic hallmark of ACS is coronary thrombosis caused by atherosclerotic plaque injury, with two types of injuries being described. The first is plaque rupture, which remains the most common cause of coronary athero-thrombosis, and the second is superficial plaque erosion which is recognized with increasing frequency. As opposed to plaque rupture, lesions that are caused by erosion do not have thin fibrous caps, abundant inflammatory cells, or a large lipid core, but rather rich in extracellular matrix, such as proteoglycans and glycosaminoglycans.

Imaging studies such as coronary computed tomographic angiography (CCTA) and diagnostic coronary catheterizations with or without optical coherence tomography (OCT) are being used increasingly in clinical practice in order to characterize the mechanism responsible for unstable/vulnerable atherosclerotic plaque.

The human gut microbiota interacts extensively with the host through metabolic exchange and co-metabolism of substrates; thereby contribute to a variety of metabolic and immunologic mechanism in the human body. CAD is a major field of interest in microbiota research, and there have been several findings that connect the gut microbiota to CAD pathophysiology. First, microbiota was associated with metabolic syndrome, namely obesity and insulin resistance. It is hypothesized that gut microbiota may increase short-chain fatty acid, that eventually increase appetite, thus causing obesity. Another hypothesis is that gut microbiota endotoxins may translocate into the bloodstream, elicit inflammatory cascade that eventually promote atherosclerosis. Second, microbiota may also have a role in the development of atherosclerosis. In patients with symptomatic atherosclerosis, there is a unique microbiome pattern that may have pro-inflammatory characteristics. Recently, a unique microbial pattern was found among patients with high cardiovascular risk profile. Third, gut microbiota metabolize dietary phosphatidylcholine (lecitine) to produce the metabolite trimethylamine-N-oxide (TMAO), which is associated with increased risk of cardiovascular events.