CME Author: Vicki Brower
Study Authors: Zeneng Wang, Nathalie Bergeron, et al.; Robert A. Koeth, Betzabe Rachel Lam-Galvez, et al.
Target Audience and Goal Statement:
Cardiologists, internists, and nutritionists
The goals were to explore the impact of chronic dietary patterns on the levels, metabolism, and renal excretion of trimethylamine N-oxide (TMAO), a byproduct of red meat digestion linked to an increased risk of heart disease; and to examine the role of the gut microbiota in generation of an intermediate metabolite, γ-butyrobetaine (γBB), and the impact of dietary history and oral l-carnitine supplementation on both γBB generation and catabolism to TMA/TMAO.
- What impact does diet have on TMAO levels, metabolism, and renal excretion?
- Are there interventions that can reduce/reverse the levels of TMAO and thus reduce the risk of cardiovascular disease (CVD)?
Study Synopsis and Perspective
Elevated plasma TMAO levels have been found in patients at risk for CVD and adverse CVD events including heart attack, stroke, and death. Animal studies suggest a role for TMAO in the pathogenesis of CVD, with manipulation of TMAO levels shown to modulate atherosclerosis and related processes.
Meta-analyses support the notion that TMAO has clinical prognostic value, showing that higher levels of circulating TMAO are associated with increased risks for CVD and death, but few studies in humans have explored the influence of chronic dietary patterns on TMA and TMAO production, metabolism, and excretion. Reducing the levels of TMAO is a theoretical beneficial therapeutic strategy to help reduce CVD morbidity and mortality.
At the Cleveland Clinic, Stanley Hazen, MD, PhD, and colleagues designed a randomized two-arm high- or low-saturated fat crossover study with 113 volunteers. The team evaluated three 4-week isocaloric diets with a washout period between each diet. All meals were prepared in a metabolic kitchen with 25% of calories derived from protein in order to study the effects of red meat, white meat, and non-meat protein on TMAO metabolism.
At the end of each diet interval the researchers quantified the levels of TMAO and other trimethylamine (TMA)-related metabolites. In addition, 13 subjects, a random subset of patients participated in heavy isotope tracer studies.
The results showed that “chronic” consumption (i.e., 4 weeks) of red meat, but not white meat or non-meat, increased plasma and urine TMAO (each greater than twofold; P< 0.0001) which were strongly correlated with two particular compounds abundant in meats like beef and pork, namely choline and carnitine.
The study also showed that red meat consumption significantly reduced fractional renal excretion of TMAO (P<0.05) (fractional excretion of a compound is simply a measure of the renal clearance of that compound divided by the glomerular filtration rate) while increasing the renal excretion of carnitine and two alternative gut microbiota-generated metabolites of carnitine, γBB and crotonobetaine (P<0.05). The oral isotope challenge showed that red or white meat, but not non-meat protein, increased the production of TMA and TMAO from carnitine (P<0.05 each) but not choline; there was no impact of dietary-saturated fat on TMAO or its metabolites.
The researchers concluded that dietary red meat increases systemic TMAO levels through enhanced dietary precursors, increased microbial TMA/TMAO production from carnitine but not choline, and reduced renal TMAO excretion. Ceasing consumption of red meat lowered plasma TMAO within 4 weeks.
In a related study in the Journal of Clinical Investigation, Hazen’s team found that carnitine is converted to TMAO via a two-step process involving gut bacteria — the first step is the same for vegetarians/vegans and those who eat meat; but in the second step, involving other bacteria, TMAO is created faster in meat-eaters than in vegetarians/vegans.
European Heart Journal 2018; DOI:10.1093/eurheartj/ehy799
Journal of Clinical Investigation 2018; DOI: 10.1172/JC194601
Study Highlights: Explanation of Findings
Hazen and colleagues confirmed in the first of the two studies described here that eating red meat is directly associated with increased levels of TMAO, a byproduct of red meat digestion that some studies have linked to a higher risk of heart disease. Only 4 weeks of consuming a heavy red-meat diet (equivalent to an eight-ounce steak a day) increased plasma and urine TMAO levels more than twofold compared with either a similar duration of eating white meat or non-meat protein.
Conversely, exchanging red meat for white meat or non-meat protein reduced blood and urine TMAO levels back to baseline levels within 4 weeks.
The researchers found that consuming a steady diet of red meat raised systemic TMAO levels by the following three mechanisms:
- Increasing nutrient density of dietary TMA precursors
- Increasing microbial TMA/TMAO production from carnitine but not choline
- Reducing renal TMAO excretion
“This is the first study to our knowledge to show that the kidneys can change how effectively they expel different compounds depending on the diet that one eats – other than salts and water,” Hazen said in a press release. “We know lifestyle factors are critical for cardiovascular health, and these findings build upon our previous research on TMAO’s link with heart disease. They provide further evidence for how dietary interventions may be an effective treatment strategy to reduce TMAO levels, and lower subsequent risk of heart disease.”
Asked for her perspective, Marion Nestle, PhD, MPH, of New York University in New York, who was not involved in the research, noted via email that observational studies have demonstrated an association between TMAO and CV risk and animal studies have suggested CV benefits from reduced TMAO levels, but proving an impact of intervention to reduce TMAO on “hard clinical endpoints” in humans would be both difficult to do and very expensive.
Still, she said, “the study provides further, but still preliminary, evidence for the health benefits of diets reduced in red meat,” and this and other microbiome studies represent “an exciting area of research, although it is too soon to draw firm conclusions.”
The crossover study by Hazen and co-authors randomized participants to three 4-week diets of the same caloric value in different orders, with the main difference the protein source: red meat, white meat (poultry), or no meat (legumes, nuts, grains, soy).
Stratifying the groups into high- vs low-saturated fat diets showed that dietary fat intake had no impact on TMAO or its metabolites.
Previous research by Hazen’s team showed that in a subset of 13 individuals out of a total of 113 healthy volunteers randomized, those who ate red meat had enhanced microbial production of TMA and TMAO from carnitine (P<0.05 for both) but not choline.
Also asked for an opinion of the research, C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center in Los Angeles, and not involved with the study, called the design “rigorous” in implicating the three pathways of a red meat diet, gut microbiota, and renal excretion in blood TMAO levels.
“Of note,” she said via email, “data to support TMAO contributing to CVD remains uncertain, so while this study is extremely useful to understand mechanistic pathways for any biomarker, causal risk factor, or risk predictor, continued investigation is needed to determine causality, as well as utility for risk prediction, as well as treatment target.”
Hazen and co-authors noted that according to one meta-analysis, assuming the changes seen in 1 month of diet can be extended, then the increases in plasma TMAO seen with the red meat diet would correspond to an approximate 4.3% difference in mortality compared with the non-meat diet.
As reported in the Journal of Clinical Investigation, Hazen’s team focused on the role of carnitine in omnivorous diets and its role in inducing an atherogenic gut microbial pattern in humans. The researchers found that dietary carnitine is converted into TMAO in a two-step pathway. The first step, by one set of gut bacteria, is the same for vegans/vegetarians and for those who eat meat. But the second step, involving other bacteria, formed TMAO more rapidly in those who eat meat.
After just 1 month of daily carnitine supplementation, however, the vegans and vegetarians in the study started producing more TMAO. “By uncovering this new pathway, we can potentially develop new treatments to interrupt this process before both the development and progression of cardiovascular disease,” Hazen said in a statement.
Taken together, the two studies illustrate mechanistically how the chronic consumption of red meat contributes to heart disease, and conversely, how modifying diet can potentially reduce CVD morbidity and mortality, the researchers said.
Original story on MedPage Today by Nicole Lou.