Long-term Changes in Gut Metabolite Predict CHD Risk

Patrice Wendling

February 20, 2020

New longitudinal data underscore the role of the gut microbial metabolite trimethylamine N-oxide (TMAO) as a predictor of coronary heart disease (CHD) but also the potential for diet to modify its deleterious effects.

Specifically, changes in TMAO over 10 years were significantly associated with CHD incidence among healthy women, even after accounting for multiple cardiovascular risk factors and dietary patterns.

At the same time, the association between TMAO and CHD was significantly strengthened by an unhealthy diet and attenuated by adherence to a healthy, or plant-based, diet.

"Actually, this is one of the best news we can get from the study because the findings suggest that, even though TMAO is related to cardiovascular disease, we can really modify the effect by eating a healthy diet," senior author Lu Qi, MD, PhD, Tulane University, New Orleans, Louisiana, told theheart.org | Medscape Cardiology.

TMAO is formed when gut bacteria metabolize nutrients, such as choline, L-carnitine, and phosphatidylcholine found in red meat, egg yolk, and high-fat dairy products. This produces trimethylamine (TMA), which is then converted into TMAO in the liver.

TMAO is a key factor in regulating lipid metabolites in the liver, and at elevated levels has been linked with higher risks for heart attack, stroke, and all-cause death. But results have been inconsistent and previous studies measured TMAO at a single time point, Qi noted.

"This is the first study, to our knowledge, to analyze the longitudinal change in TMAO with cardiovascular disease," said Qi, who is also the director of the Obesity Research Centre at Tulane.

The study was published February 17 in the Journal of the American College of Cardiology.

Commenting to theheart.org | Medscape Cardiology, W.H. Wilson Tang, MD, Cleveland Clinic, Ohio, a TMAO researcher who was not involved in the study, said the findings extend and validate the original hypothesis that there is a diet–microbial interaction that leads to accumulation and development of coronary artery disease.

"The biggest implication here is that right now when we counsel our patients, we really don't have any gauge as to what exactly is the abnormality and how to target those at risk," he said. "If you have someone with high cholesterol or high sugars, you can measure and target them with different medications and follow them to achieve a target range. We have never had something like that in specific dietary patterns."

"So I think this actually creates an opportunity for us to investigate whether measuring these metabolites can provide some guidance for that, and what processes contribute to metabolite changes."

The study involved 760 healthy women in the prospective Nurses' Health Study who reported dietary habits and provided blood samples from 1989 to 1990 and again from 2000 to 2002. Ten-year changes in TMAO were calculated and categorized into tertiles for 380 cases of incident CHD occurring after the second blood sample through 2016 and 380 age- and smoking status-matched controls.

Results show that CHD cases had a significant 10-year increase in TMAO concentrations from the first blood sample to the second blood sample (P = .009).

Specifically, every 1-standard deviation increase in TMAO was associated with a 33% increased risk for CHD (relative risk [RR], 1.33; 95% confidence interval [CI], 1.06 - 1.67).

Women with the largest increases in TMAO (tertile 3, median change, 3.7 µmol/L) had a 67% higher risk of incident CHD compared with those with stable TMAO levels (median change, 0.1 µmol/L) after adjusting for demographic, diet, and lifestyle factors (RR, 1.67; 95% CI, 1.13 - 2.44).

In the fully adjusted model that further controlled for obesity and metabolic risk, their CHD risk was 58% higher (RR, 1.58; 95% CI, 1.05 - 2.38).

A dose-response analysis showed a strong linear relationship between TMAO change and CHD risk in the fully adjusted model.

In a spline analysis, both increases and decreases in TMAO showed significant associations with either an increased or decreased CHD risk after adjustment, the authors reported.

Notably, women with high TMAO levels (tertile 3) at both time points were at a significantly higher CHD risk compared with women with sustained low TMAO levels (fully adjusted RR, 1.79, 95% CI, 1.08 - 2.96).

The researchers also found significant interactions between TMAO changes and adherence to healthy dietary patterns assessed by the Alternate Healthy Eating Index (P = .008) and the healthy Plant-based Diet Index (P = .04). Greater increases in TMAO were significantly association with CHD risk among women with lower adherence to these dietary habits, whereas the association was not significant among those with higher adherence.

"These results support the importance of modulating TMAO levels by interventions in the prevention of subsequent CHD events," the authors, led by Yoriko Heianza, RD, PhD, also with Tulane University, said.

In an accompanying editorial, Paul Heidenreich, MD, MS, and Petra Mamic, MD, from Stanford University School of Medicine, California, point out that recently developed inhibitors of TMAO-producing bacterial enzymes reduced TMAO levels and attenuated atherosclerotic plaque development and platelet aggregation in mice models.

"Arguably, a more sustainable and pragmatic approach to TMAO modulation may be through targeted dietary interventions," they said. "Vegans and vegetarians, compared with omnivores, have much lower TMAO levels. Red meat especially has been associated with high TMAO levels, and substantial decrease in TMAO was seen within several weeks of discontinuation of red meat intake."

Notably, 3,3-dimethyl-1-butanol (DMB), a structural analog of choline and one of the inhibitors studied in the mice models, is also present in some cold-pressed extra virgin olive oils, red wine, and balsamic vinegar — staples of healthy diets such as the Mediterranean diet.

Whereas largely plant-based diets are known to induce shifts in the gut microbiome, on the individual level, gut microbiota changes and downstream physiologic responses to dietary interventions are highly variable, Heidenreich and Mamic observed.

"Although the idea of personalized nutrition in practice may still be beyond our reach, we should not let perfect be the enemy of good," they added. "The results from Heianza et al should encourage us to continue to advocate for a more widespread adoption of healthy eating patterns."

The study authors note that further research is needed to confirm the findings in male cohorts and a more representative sample of the US population. Other study limitations are the use of self-reported assessments of dietary patterns and other covariates, and the lack of information on timing and trajectory of TMAO changes.

"We are now doing a series of studies to investigate the potential mechanisms to see what happens if we change the diet and how changing diet affects TMAO and what happens in between — the precise mechanisms," Qi said. "That is the next step."

The study is supported by National Institutes of Health (NIH) grants from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; an NIH-shared instrumentation grant; the Boston Obesity Nutrition Research Center; and a United States–Israel Binational Science Foundation Grant. Heianza was a recipient of a Grant-in-Aid for Scientific Research, a Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science, and the 2019 AHA postdoctoral fellowship award. All other authors, Heidenreich, and Mamic reported have disclosed no relevant financial relationships. Tang reported that the TMAO assay was measured at his institution, but that he has no personal conflicts of interest.

J Am Coll Cardiol. Published online February 17, 2020. Abstract, Editorial

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