THE MICROBIOME AND DISEASE, SERIES #4
by Alon Steinberg, Sabine Hazan
In this article, we discuss further understanding the gut microbiome along with its effect on metabolites and cardiovascular health. This understanding will give us opportunities to develop new test and therapeutic approaches to arteriosclerosis. In the future, stool transplantation with lean or low risk for cardiovascular disease microflora may be a way of treating patients who are susceptible to arteriosclerosis.
Alon Steinberg MD, Cardiology Associates Medical Group, Ventura Clinical Trials, expertcardiologist.com Sabine Hazan, MD, Gastroenterology/Hepatology/ Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Ventura, CA
Despite great focus and multiple treatments for coronary artery disease and its risk factors, the residual number of deaths is very large. Cardiovascular disease is the number one cause of death in the world.1 Our well-known risk factors for arteriosclerosis do not always explain the degree of cardiovascular disease development and risk of myocardial infarction and death. Researchers and physicians are looking to uncover novel reasons and risk factors in hopes to explain why patients develop arteriosclerosis and ruptured plaque. There has been an interest in inflammation including obesity and metabolic syndrome as contributing factors. As eloquently summarized in last issue of Practical Gastroenterology,2 the microbiome may contribute significantly to these risks.
Humans have a symbiotic relationship with our gut microflora. The gut microbiome helps metabolize fuels, aids with absorption and helps create important vitamins and amino acids. The microbiota breaks down toxins and is a barrier against invading bacteria. What we eat has a large impact on the development of heart disease. Can the study of the microbiome help us understand why we develop heart disease? Can we can work to manipulate the microbiome to prevent heart disease?
There appears to be lean and obese microbiota.3 In study with mice, lean and obese donors had their cecal microbes transplanted to germ-free recipients. Those mice colonized with obese microbiome developed obesity while those with lean donors remained lean. This documents that our microbiome can affect what we absorb and is a factor in our metabolism. This study also showed that this may be transmissible and changed.3 In a human study, stool transplant from lean donors to obese recipients with metabolic syndrome showed significant and persistent improvement in insulin sensitivity.4 This shows that changing gut microorganisms can alter mechanisms that can transform and improve metabolism. Further understanding hopefully with can lead to developing intestinal microbiota as a therapeutic agent to reduction of obesity, metabolic syndrome, inflammation and cardiovascular disease.
There is a saying that the best way to a man's heart is through his stomach. But we now know that is not just what you eat but what your gut microbiome lets pass and creates. Metobolomic studies have now revealed effective routes linked to cardiovascular disease. Metabolites choline, TMAO, and betaine were shown to predict risk for cardiovascular disease in an independent large clinical cohort.5 These metabolites are linked to lecithin (or phoshaphatidylcholine) metabolism. Our Western diet is full of lecithin. Gut microbes use lecithin to create trimethylamine (TMA) which gets absorbed by the gut. While in blood circulation, the liver then converts TMA to TMAO.
Dietary supplementation with these metabolites in mice showed an upregulation of multiple macrophage scavenger receptors and creation of foam cells and arteriosclerosis. When these diet supplements were given to mice with gut free of flora, dietary metabolites were not created and thus did not promote arteriosclerosis.5 In a human study, suppression of intestinal microbiota with oral broad-spectrum antibiotics showed plasma levels of TMAO were markedly suppressed. TMAO rise reappeared after withdrawal of antibiotics.6
Further testing has been done with Trimethylamine N-oxide (TMAO). Increased levels of TMAO were associated with an increased risk of major adverse cardiovascular events6 and may be a stronger risk factor than LDL and C-reactive protein. A recent meta-analysis showed TMAO increased cardiovascular risk and mortality.7 This gut metabolite that has been associated with accelerated arteriosclerosis, enhanced platelet hyper-reactivity and thrombosis risk.8
One way to control TMAO levels is diet. Vegetarians, vegans and those on Mediterranean diet9 are associated with lower TMAO levels. TMAO decrease may explain the reduction in cardiovascular risk with the Mediterranean diet.
Another way to target TMAO is antibiotics. Prior antibiotic trials for prevention of coronary disease events have been disappointing. It is thought that a possible and intriguing risk factor for development of arteriosclerosis is inflammation due to infectious disease (e.g. chlamydia). Randomized trials with antibiotics in humans targeting certain bacteria have not shown to have a significant effect on cardiovascular outcomes and may cause increased risk.10 These trials were targeting specific organisms and not on adjusting the makeup of intestinal microbiota. The risks of microflora change (and QT prolongation) did not outweigh of the benefits. Future studies with antibiotics aiming at reducing TMAO may be in order but other therapeutic approaches may be better.
We need to further understand the gut microbiome better along with its effect on metabolites and cardiovascular health. This understanding will give us opportunities to develop new test and therapeutic approaches to arteriosclerosis. Medications can be developed against microbial enzymes creating dangerous metabolites like TMA and TMAO, blocking diet induced arteriosclerosis. Stool transplantation with lean or low risk for cardiovascular disease microflora may be a way in the future of treating patients who are susceptible to arteriosclerosis.
See the article Tables, Images and References in the PDF