How the Microbiome Influences Cardiovascular Disease

Thomas F. Luscher, MD

The significance of the gut microbiome as it relates to cardiovascular disease is infrequently prevalent in research and development of new therapies and treatment guidelines for at-risk patients.

But its link to very diseases and events cardiologists aim to reduce is becoming more undeniable.

In a virtual session during the European Society of Cardiology (ESC) 2020 Congress this week, Thomas F. Luscher, MD, of the Royal Bromptom and Harefield Hospitals and Imperial College, as well as the University of Zurich in Switzerland, highlighted a pair of microbiome-based factors which play closely to the development of cardiovascular disease.

Luscher began by scaling the significance of the microbiome in overall health: individuals have an estimated 100 trillion bacterial cells—or a ratio of 3:1 versus human body cells.

It is most prominently being discussed now as another effect of coronavirus 2019 (COVID-19), as hospitalized patients have been observed to experience an overgrowth of bacteria over an extended period of time.

“Whether this is also affecting the outcome of these patients needs to be investigated, but it’s interesting that infections change our microbiome,” Luscher said.

Regarding cardiovascular disease, choline (TMA/TMAO) is among the most clinically discernible drivers of events and risks. It is processed to stimulate plaque formation and thrombosis, and is currently associated with raised prevalence of atherosclerosis, as well as cholesterol accumulation in arterial wall cells.

TMAO levels have become highly predictive of individuals’ major adverse cardiovascular event (MACE) risks. The gut flora metabolism of phosphatidylcholine is shown to promote cardiovascular disease in mice; presumably, the effect in humans is even more significant.

Luscher and colleagues have observed in research that the amino acide phenylalanine is converted into phenylacetyl-glutamine by the gut microbiota. That activates the adrenergic receptors responsible for platelet aggregation, a crucial facet of acute myocardial infarction (AMI).

“We have expanded these studies with the Cleveland Clinic to include trimethyllysine (TML), which is a precursor of TMAO,” Luscher said. “Both cohorts from the Cleveland Clinic and our Swiss cohort show that TML and TMAO have additive effects, so that the worse outcomes are in those with high TML and TMAO levels in plasma.”

These are common in red meats. One study comparing carnitine-rich red meat versus white meat, when measuring healthy volunteer plasma levels, showed TMAO was raised among those eating hamburgers and steaks, versus those eating fish and chicken.

Secondly, lipopolysaccharide (LPS), contained in the cell membrane of Gram-negative bacteria, is critical for acute coronary syndrome (ACS). Toll-like receptor 4 (TLR-4) is expressly affected by LPS, leading to the development of cytokines and protases—leading to plaque ruptures, Luscher explained.

When discussing what can be done to influence positive gut microbiota health as it relates to cardiology, Luscher pointed to a quartet of factors: therapeutic intervention, dietary drugs, microbiome modulation via probiotics, and microbiome transplantation.

Drug-wise, metformin has been associated with alteration of the gut microbiome in treatment-naïve patients with type 2 diabetes.

“This is very interesting,” Luscher said. “And if you take the microbiome of those treated with metformin for some time and give it to mice, you can see their glucose tolerance test is markedly improved versus the mice who received their own microbiome.”

Statin, the most commonly prescribed cardiovascular therapy, has erstwhile been associated lower gut microbiota dysbiosis prevalence—a finding verified in recent cohorts.

Regardless of the approaches taken to resolve cardiovascular risk or in promoting preventive health, an emphasis needs to be put on how gut microbiota is influenced.

“The microbiome is important,” Luscher concluded. “It’s affected by drugs, and we should consider it as a new factor in understanding cardiovascular disease, and also as a new drug target.”