Diet with red meat as main protein source increases levels of TMAO, which is linked to atherogenesis
Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women
Introduction and methods
Trimethylamine N-oxide (TMAO) is a metabolite produced by gut microbiota. Plasma TMAO levels are elevated in subjects at risk for CVD events, and mechanistic links to the pathogenesis of atherosclerotic heart disease have been described [1-5]. Moreover, a clinical prognostic value of circulating TMAO levels for both CVD and mortality risk has been described for several cohorts and continents [6-8]. Hence, decreasing systemic levels of TMAO may be a therapeutic strategy to lower risk of development and progression of atherosclerotic heart disease.
Gut microbiota form trimethylamine (TMA) out of TMA-containing nutrient precursors [1-3,9], such as phosphatidylcholine, which is abundant in both plant an animal products. Beef and other meats, liver and egg yolk have higher total choline content . Red meat contains high levels of carnitine, another nutrient precursor of TMA . Consequently, a diet rich in meat, and particularly red meat, provides high levels of both choline and carnitine precursors for TMA and TMAO generation.
Evidence that systematically examined the influence of chronic dietary patterns on TMA and TMAO production, metabolism and renal excretion is limited. Different plasma TMAO levels have been observed when comparing omnivores and vegans/vegetarians [3, 11].
This study investigated in a randomized, three-period cross-over design, whether chronic (4 week) ingestion of an isocaloric diet containing protein derived predominantly from either red meat, white meat or non-meat sources affects systemic levels of TMAO. Meals were prepared and provided for by the study. Many of the TMAO nutrients precursors and their overall metabolism and renal excretion rates in vivo were also studied. 113 Healthy participants (all omnivores) first consumed a 2-week baseline (run-in) diet, after which they were assigned to three experimental diets in random order, each for 4 weeks. The diet periods were separated by a 2-7 weeks washout period, in which participants were instructed to eat their habitual diet.
- After 1 month of consuming the red meat diet, the majority of subjects showed an increase in plasma TMAO levels, on average by about 3-fold compared with the white meat or non-meat diet (both P<0.0001). Some subjects showed an over 10-fold increase. The red meat diet also results in significant increases in urine TMAO levels.
- TMAO levels were quite consistent within subjects; day-to-day variability was small.
- With regard to metabolites, the red meat diet was associated with modest but statistically significant reductions in plasma betaine and urine choline concentrations, as compared with the non-meat and white meat diets. The carnitine-related metabolites γ-butyrobetaine and crotonobetaine were significantly increased after the red meat diet in both plasma and urine.
- The order of the diets did not significantly affect the observed effects of the diets on the monitored metabolites. Highest TMAO levels were observed after completion of the red meat diet, and a marked reduction in TMAO was seen when another diet was consumed.
- Consuming 4 weeks of a low- vs. high-saturated fat diets did not affect plasma levels of TMAO or the TMA-containing compounds.
- The fractional renal excretion rate (renal clearance divided by GFR, thus the fraction excreted) of TMAO was significantly reduced after consumption of the red vs white or non-meat diets. The red meat diet, in comparison with the other diets, differentially affected the fractional renal excretion of the other metabolites, for some it was increased, for others it was unaffected.
- In isotope tracer studies, higher microbial production of TMA and TMAO from carnitine, but not choline, was seen after the red meat diet.
A diet in which proteins are mainly derived from red meat results in substantial increases in fasting plasma and urine TMAO levels, as compared with isocaloric white meat and non-meat diets. This study into this meta-organismal metabolism of TMAO suggests that the red meat diet raises TMAO levels via three mechanisms: enhanced nutrient density of dietary TMA precursors, higher microbial TMA/TMAO production from carnitine (but not choline) and lower renal TMAO excretion.
The kidneys appeared to dynamically regulate fractional excretion of TMAO and metabolites. The observed reduced renal clearance of TMAO after a month of red meat diet, suggests that the kidney becomes less efficient at eliminating TMAO, while the opposite effect on other metabolites was observed.
Davies and Lüscher  summarize recent insights in the biological effects of metabolites produced by gut bacteria, including the links between TMAO and CV risk.
By means of an isocaloric dietary intervention study, Wang et al. showed that a red meat-enriched diet significantly increases plasma and urine TMAO levels. The data on switching from a red meat diet to a white meat or non-meat diet suggested that such dietary changes may exert beneficial effects by modifying the plasma levels of the metabolite.
Davies and Lüscher praise the authors for their use of the isocaloric study design and provisioning the foods, as compared with other approaches, like food questionnaires. They note that this set up provides a proof that a lean red meat-based diet (with either low or high saturated fats) leads to substantial increases in plasma TMAO.
The study raises several interesting questions, for instance with regard to the high individual variation in plasma TMAO levels in subjects on the red meat diet. It would be interesting to relate these differences to specifics at the level of the microbiome, or genetic differences of the host. Another crucial question is what can be considered a healthy microbiome with regard to TMAO levels.
Further research into the role of TMAO in CV disease may study the molecular mechanisms of atherosclerotic plaque formation, with the notion that the TMAO-mediated pathway appears to be distinct from conventional CV risk factors. Moreover, it remains to be established whether interventions should target the products of the microbiome, or the microbiome itself. Some dietary approaches are known to affect the microbiome and/or TMAO, and some probiotics can lower TMA and TMAO plasma levels. Microbial TMA lyase inhibitors could form a pharmacological approach. Alternatively, transplantation of fecal microbiota can restore dysbiosis caused by a Western diet high in processed carbohydrates and animal products.
This study proves that red meat, through L-carnitine, is the major source of elevated TMAO levels in a healthy Western population. This finding warrants further study in patients with CV disease.