TMAO3: Diet, Stress and the Obese Gut
Three recent “high-impact” research articles by Wang et al., Koeth et al., and Tang et al. have demonstrated associations between increased blood levels of trimethylamine-N-oxide (TMAO) and cardiovascular disease (CVD) [1-3]. This work has led to increased interest in the interplay between diet, gut bacteria and CVD. The research by these authors is both elegant and provocative, yet we question if these reports tell the whole tale of TMAO and the possible contributors to increased concentrations of this compound in the blood, in fact multiple factors appear to contribute to the increase in TMAO: Diet (Too Much Animal Oil); the Obese Gut (Too Many Aberrant Organisms) and Stress (Too Much Ambient Oppression).
Proposed Contributions to Blood TMAO Concentration by Diet, the Gut and Stress
Diet: Too Much Animal Oil
Because TMAO is produced by gut bacterial metabolism of two common nutrients in red meat and eggs (i.e., l-carnitine and phosphotidylcholine), diets high in animal products have been implicated for the association between blood TMAO concentrations and CVD. It is well known that diets high in animal products are associated with increased risk of CVD, due to several possible mechanisms including increased intake of saturated fat and cholesterol, pro-oxidative iron, and increased amounts of glycation end products when cooked - all potential contributors to a pro-inflammatory state.[4, 5] Although the evidence about egg intake and CVD risk is mixed, several recent studies convincingly demonstrate increased risk, especially for egg yolk consumption.[6, 7] However, these new articles suggest a potentially new mechanism responsible for CVD risks from meat and egg consumption, increased TMAO, with subsequent increases in white blood cell (i.e., immune cell)-mediated atherosclerosis. This mechanism seems feasible.
However, consumption of other foods - including seafood (rich in heart-friendly omega-3 fatty acids) - also increases production of TMAO. Despite this, the focus of the recent discussion has remained on the intake of red meat and other land-based animal foods, with less emphasis placed on other factors that could contribute to the increased CVD seen with higher TMAO concentrations. In reviewing the article by Tang et al., other alternative mechanisms may also contribute to the associations measured between TMAO and CVD, notably the impact stress and abdominal obesity have on establishing the bacteria that produce TMAO, and mechanisms by which the TMAO may enter the blood stream in higher concentrations.
The Obese Gut: Too Many Aberrant Organisms
The relationship between gut bacteria and obesity has become an area of great interest due to findings in animal models demonstrating that obesity can be caused by dietary-induced changes in the gut microbiota , and that inoculation of sterile laboratory animals with the gut organisms of other animals can induce obesity and insulin resistance, despite eating less food!  The mechanisms thought to be responsible for this association are numerous, and were recently reviewed by Molinaro et al.  Amongst the mechanisms include increased gut permeability and absorption of bacterial byproducts called “endotoxins”. Endotoxins induce inflammation in the liver, and increase the production of pro-atherogenic lipid particles, i.e., LDL. Endotoxin concentration in the blood has been linked to increased CVD and inflammation in people with increased obesity, liver disease, chronic kidney disease, and type 2 diabetes.
Notably when differences in body mass index (i.e., BMI, a measure of obesity) were considered in the research by Tang et al., the positive relationship between TMAO and CVD was greatly diminished, and only remained significant in the group with the highest blood concentration of TMAO. As waist circumference is considered a better biomarker of abdominal obesity than BMI, adjustment for waist circumference may have been a better choice for their statistical analysis.
Stress: Too Much Ambient Oppression
It is well known that psychological stress caused changes in digestive function, including changes in gut motility, permeability, oxidative stress and susceptibility to infection. Supporting a relationship between acute stress and TMAO, blood TMAO concentration increased in models of surgical stress. Rezzi et al. recently compared differences in blood concentration of various substances, including nutrients, lipids, etc., between healthy humans during low stress, and during moderate stress. During moderate stress, gut permeability increased, as did blood concentrations of choline, a precursor to TMAO (unfortunately TMAO itself was not measured)!
Unfortunately, Tang et al. did not adjust their results for differences in perceived stress between the groups, despite stress being an established risk factor for CVD.[16, 17] To better understand TMAO-associated CVD risk, the contribution of stress to increased gut permeability (and thus potentially increased TMAO) should be considered in future studies.
Are you suggesting red meat and eggs don't cause CVD?
No. Although we are suggesting TMAO itself may not be the culprit, rather may be a biomarker of an interaction between diet, the obese gut and stress - what we’re calling “TMAO3”. We believe that this complex interaction may better describe the development of CVD, rather than pinning it on a specific compound. To reiterate some of the research points that support this hypothesis:
- Stress is known to increase gut permeability, blood choline and LDL in humans;
- TMAO in the blood is higher following stress in animals ;
- Stress is associated with increased risk of obesity [18-20];
- Obesity is associated with increased endotoxin ;
- Obese animals have higher TMAO concentrations than lean animals ; and
- Both stress and obesity are associated with increased CVD .
How can I redeuce my risk of increased TMAO in the blood?
Although Wang et al. used antibiotics to demonstrate the role of gut bacteria in the production of TMAO, using antibiotics more frequently is not the solution to CVD! In fact, because stress reduces blood flow to the gut, and a poorly perfused gut is more susceptible to severe infection [22-24], using antibiotics, rather than addressing stress and diet, may actually contribute to severe gut infection, extreme gut permeability and even systemic infection or sepsis, if the microbiota is not healthy. However, there are actually several strategies to modify the potentially potent interaction between stress, diet, the microbiota, gut permeability, and CVD:
- Eat a predominately plant-based diet. Although red meat and eggs may not be exclusively causative, they are higher in numerous pro-inflammatory compounds, and thus prudent intake is still warranted. Not only are plant-based foods lower in TMAO precursors, but they are also higher in prebiotics that support a healthy gut microbiota.
- Reduce stress. Stress may be the causative link between the gut, endotoxins, obesity and CVD. There are a number of easy, effective stress-reducing techniques available. See Complementary Corner article on Stress Reduction
- Eat plant-based foods especially during times of stress. Although challenging during stressful moments when we want comfort foods, increased intake of animal products during stressful times may be particularly harmful.
TMAO? Tell us something we haven’t heard already - red meat and stress are bad, and a healthy gut is important. Although this approach may take the shine off TMAO as a nifty biomarker, it is more likely to address the cause and not the symptoms.
Ryan Bradley, ND, MPH and Bill Walter, ND
Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. He is Assistant Director of Research at the National College of Natural Medicine in Portland, OR. In addition to his research, he is a practicing clinician specializing in natural and integrative approaches to treating type 2 diabetes, chronic kidney disease and heart disease at Pacific Pearl La Jolla.
1. Tang, W.H., et al., Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med, 2013. 368(17): p. 1575-84.
2. Koeth, R.A., et al., Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med, 2013.
3. Wang, Z., et al., Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 2011. 472(7341): p. 57-63.
4. de Oliveira Otto, M.C., et al., Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr, 2012. 96(2): p. 397-404.
5. Micha, R., G. Michas, and D. Mozaffarian, Unprocessed red and processed meats and risk of coronary artery disease and type 2 diabetes--an updated review of the evidence. Curr Atheroscler Rep, 2012. 14(6): p. 515-24.
6. Spence, J.D., D.J. Jenkins, and J. Davignon, Dietary cholesterol and egg yolks: not for patients at risk of vascular disease. Can J Cardiol, 2010. 26(9): p. e336-9.
7. Spence, J.D., D.J. Jenkins, and J. Davignon, Egg yolk consumption and carotid plaque. Atherosclerosis, 2012. 224(2): p. 469-73.
8. Zhang, A.Q., S.C. Mitchell, and R.L. Smith, Dietary precursors of trimethylamine in man: a pilot study. Food Chem Toxicol, 1999. 37(5): p. 515-20.
9. Kim, K.A., et al., High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One, 2012. 7(10): p. e47713.
10. Backhed, F., et al., The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A, 2004. 101(44): p. 15718-23.
11. Molinaro, F., et al., Probiotics, prebiotics, energy balance, and obesity: mechanistic insights and therapeutic implications. Gastroenterol Clin North Am, 2012. 41(4): p. 843-54.
12. McIntyre, C.W., et al., Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol, 2011. 6(1): p. 133-41.
13. Hiki, N., et al., Pathophysiological relevance of the CD14 receptor in surgical patients: biological activity of endotoxin is regulated by the CD14 receptor. J Endotoxin Res, 2001. 7(6): p. 461-6.
14. Kinross, J.M., et al., Global metabolic phenotyping in an experimental laparotomy model of surgical trauma. J Proteome Res, 2011. 10(1): p. 277-87.
15. Rezzi, S., et al., Metabotyping of biofluids reveals stress-based differences in gut permeability in healthy individuals. J Proteome Res, 2009. 8(10): p. 4799-809.
16. Rosengren, A., et al., Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet, 2004. 364(9438): p. 953-62.
17. Yusuf, S., et al., Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 2004. 364(9438): p. 937-52.
18. Barrington, W.E., et al., Perceived stress, behavior, and body mass index among adults participating in a worksite obesity prevention program, Seattle, 2005-2007. Prev Chronic Dis, 2012. 9: p. E152.
19. Chen, Y. and L. Qian, Association between lifetime stress and obesity in Canadians. Prev Med, 2012. 55(5): p. 464-7.
20. Gebreab, S.Y., et al., The contribution of stress to the social patterning of clinical and subclinical CVD risk factors in African Americans: the Jackson Heart Study. Soc Sci Med, 2012. 75(9): p. 1697-707.
21. He, Q., et al., Comparison of serum metabolite compositions between obese and lean growing pigs using an NMR-based metabonomic approach. J Nutr Biochem, 2012. 23(2): p. 133-9.
22. Ansaldi, M., et al., Aerobic TMAO respiration in Escherichia coli. Mol Microbiol, 2007. 66(2): p. 484-94.
23. Sellars, M.J., S.J. Hall, and D.J. Kelly, Growth of Campylobacter jejuni supported by respiration of fumarate, nitrate, nitrite, trimethylamine-N-oxide, or dimethyl sulfoxide requires oxygen. J Bacteriol, 2002. 184(15): p. 4187-96.
24. Seal, J.B., et al., Agent-based dynamic knowledge representation of Pseudomonas aeruginosa virulence activation in the stressed gut: Towards characterizing host-pathogen interactions in gut-derived sepsis. Theor Biol Med Model, 2011. 8: p. 33.
25. Flint, H.J., The impact of nutrition on the human microbiome. Nutr Rev, 2012. 70 Suppl 1: p. S10-3.