Ongoing Research Points to Key Role of Gut Microbes in Cardiovascular Health
Microbes that normally reside in the gut are receiving considerable attention as important contributors to cardiovascular health and disease. From digestion and metabolism to pain perception and cognition, there may be no aspect of human biology that is free from the effects of these organisms.
Regarding the cardiovascular system, effects may result from microbial imbalances in the digestive tract that promote systemic inflammation, and from byproducts generated from gut bacteria, as well, as they metabolize certain dietary components.
“Microbial transplantation studies in animals show a causal contribution of gut microbes to processes like thrombosis and atherosclerosis,” said Stanley Hazen, MD, PhD, who is Chairman of the Department of Cellular and Molecular Medicine at the Cleveland Clinic. Studies have also demonstrated causal effects on metabolic disorders including obesity and insulin resistance, but the magnitude of these effects in humans is unclear. In addition, research suggests that the relative proportions of specific bacterial taxa in the gut microbiome may determine the propensity toward such conditions. For example, Jingyuan Fu, PhD, an associate professor of genetics at the University of Groningen in The Netherlands, and her colleagues recently identified 34 bacterial taxa associated with body mass index and blood lipids in the general population. “Gut microbes seem to make a significant contribution, even stronger than clinical risk factors and genetics, to individual variations in body mass index and blood levels of triglycerides and HDL, but they have little effect on LDL or total cholesterol levels,” said Fu. Much more work is needed, however, to fully map out the details behind which bacterial types are detrimental and which are beneficial.
Hazen’s research is providing some clues concerning the mechanisms that may be involved in at least some of the links between gut bacteria and cardiovascular parameters. His research team has shown that when gut bacteria metabolize specific nutrients abundant in meat and animal products including choline, phosphatidylcholine, and l-carnitine, they produce a substance called trimethylamine-N-oxide (TMAO) that promotes atherosclerosis.
“Looking at multiple inbred strains of mice, we can observe that variations in TMAO levels across the different inbred strains account for about the same contribution to variation in atherosclerotic plaque development as changes in cholesterol levels do,” said Hazen. In the investigators’ recent work in humans, TMAO served as the strongest tie to coronary artery atherosclerotic burden in head-to-head comparisons with other laboratory parameters and traditional risk factors.
The mechanisms through which the TMAO pathway may affect cardiovascular health are quite extensive. “Changes in sterol metabolism and transport at the level of the gut, liver, and artery wall have been shown,” said Hazen. “More recently, TMAO has been shown to change platelet reactivity and responsiveness to known clot-inducing agents, as well as to promote arterial endothelial cell activation and inflammatory gene expression.” The TMAO pathway also fosters fibrosis in end-organ tissues and facilitates kidney function decline, adverse ventricular remodeling, and heart failure after long-term exposure.
“TMAO is no doubt just the tip of the iceberg,” said Hazen. “There is every reason to believe that numerous other microbial pathways exist that impact cardiovascular disease and metabolic phenotypes. We just need to learn the participants and players involved, and it will no doubt result in numerous opportunities for new and improved diagnostics and therapeutics in the field of cardiometabolic diseases.”
Short-chain fatty acids (SCFAs), which are generated when bacteria ferment dietary fibers, may also play an important role in the gut microbiome’s link to cardiovascular health. “SCFAs not only serve as an energy source for the host but also act as signaling molecules to regulate inflammation,” explained Fu. “Research has shown both in vivo and in vitro that SCFAs have beneficial effects in the host and could lower the risk of cardiovascular disease.”
Many efforts are underway to develop therapeutic strategies that manipulate gut bacteria to improve human health. “These strategies range from dietary interventions, probiotics and prebiotics, fecal transplantation, and small-molecule drugs targeting specific bacterial pathways,” said Fu.
Recent studies show that chronic dietary changes that incorporate healthy options reduce TMAO levels. When Hazen and his colleagues compared how the guts of omnivores, vegetarians, and vegans processed l-carnitine, they found the omnivores’ gut bacteria led to generation of TMAO and certain other metabolites, whereas the vegetarians’ and vegans’ bacteria did not. Studies also indicate that adhering to the Mediterranean diet boosts levels of SCFAs and decreases TMAO.
In more focused research, a compound developed by Hazen’s team that is also found in some vinegars and olive oils effectively blocked the gut bacterial pathway that produces TMAO in mice and prevented atherosclerosis. Similarly, resveratrol, a compound found in red wine that has antioxidant properties, was found to alter the ratio of different bacterial types in the gut and attenuate TMAO-induced atherosclerosis. Existing medications, including statins, are also known to impact the gut microbiome, but their effects on TMAO remain to be determined.
TMAO and other microbial-dependent products that can be measured in the blood might also be used as cardiovascular diagnostic or prognostic markers. In several large clinical studies, plasma levels of TMAO were predictive of subsequent heart attack, stroke, and death, even after adjustments for traditional risk factors.
Although much of this work is generating promising clinical leads, teasing out the details behind how the complex gut microbiome affects the cardiovascular system, and how to use that information to meaningfully improve health, will be no easy task. There are ≈100 trillion microbes representing an estimated 5000 species living in the human gastrointestinal tract.
“We need to look at human health and physiology in a new and more global way, and appreciate that we are actually walking communities, comprised not only of Homo sapiens cells, but also trillions of microorganism inhabitants,” said Hazen. “Our overall metabolism and how we experience a meal, which is our largest environmental exposure, is linked not only to our genes, but to the gut microbial filter. We live in the ‘bus exhaust’ of our microbes within, and differences in disease susceptibility between us appear in part to depend on the microbial products we absorb into our bodies with every meal.” n
Circulation is available at http://circ.ahajournals.org.
- © 2016 American Heart Association, Inc.