Gut microbiota affect atherogenesis

Koeth RA, Wang Z, Levison BS et al.
Nat Med. 2013 Apr 7. doi: 10.1038/nm.3145. [Epub ahead of print]

Background

A recent meta-analysis of prospective cohort studies challenged the widely presumed association between dietary saturated fat intake and cardiovascular disease (CVD) risk [1]. If it is not the cholesterol and saturated fat content of red meat that can account for the association between meat consumption and CVD, then what other environmental exposure linked to meat exposure may?
This study explored the participation of commensal intestinal microbiota in modifying the diet-host interaction with respect to red meat consumption.
Recently, a pathway has been reported that links microbiota metabolism of dietary choline to CVD pathogenesis [2]. Choline is metabolised to produce TMAO (trimethylamine-N-oxide), which is proatherogenic and associated with CV risk [3].
l-carnitine is an abundant nutrient in red meat, with a similar structure to choline. It is important for transport of fatty acids into the mitochondria [3,4]. Because of the increased l-carnitine ingestion and supplementation in industrialised societies, the authors hypothesised that and examined whether l-carnitine is metabolised by gut microbiota to produce TMAO, possibly with associated health risks.

Main results

• Production of TMAO from l-carnitine depends on intestinal microbiota and could be suppressed with antibiotics in human volunteers undergoing an l-carnitine-challenge.
• Capacity to produce TMAO varied among individuals. Omnivores showed increased TMAO production and concentrations, whereas long-term vegans and vegetarians had clearly reduced capacity to produce TMAO after a carnitine-challenge.
• Analysis of genetic enterotypes revealed different microbial compositions for vegans and vegetarians versus omnivores, suggesting that dietary habits may modulate both intestinal microbiota composition and thereby the ability to synthesize TMAO from dietary carnitine.
• The necessity of gut microbiota for TMAO production was confirmed in mice. TMAO was shown to be inducible in previously germ-free mice.
• In a large cohort of stable patients undergoing cardiac evaluation, significant dose-dependent associations were observed between l-carnitine concentration and risk of prevalent coronary artery disease (CAD), peripheral artery disease (PAD) and overall CVD, even after correction for common CVD risk factors.
  Elevated fasting plasma l-carnitine concentration was an independent predictor of major adverse cardiac events (MACE), even after correction for common CVD risk factors. Statistical analyses suggest that these associations are mostly driven by TMAO concentrations.
• Mice fed with l-carnitine-supplemented diets showed ~30% less reverse cholesterol transport (RCT) than mice on a control diet. A TMAO-containing diet gave a similar RCT reduction. Gene expression studies suggested that this TMAO-effect on cholesterol elimination from the body occurs through dysregulation of bile acid synthesis.

Conclusion

This study reveals a pathway potentially linking dietary red meat ingestion with atherosclerosis pathogenesis. The proatherosclerotic metabolite TMAO can be produced from dietary l-carnitine by gut microbiota. TMAO changes cholesterol and sterol metabolism, with a net effect of increasing atherosclerosis.
Since l-carnitine is a common over-the-counter dietary supplement, these findings call for an investigation of the safety of chronic l-carnitine supplementation, as high oral doses could in certain circumstances foster growth of gut microbiota with enhanced capacity to produce TMAO and potentially accelerate atherogenesis.

References

1.Siri-Tarino, PW, Sun, Q, Hu, FB, Krauss, RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am. J. Clin. Nutr. 91, 535–546 (2010).
2.Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
3. Bremer, J. Carnitine—metabolism and functions. Physiol. Rev. 63, 1420–1480 (1983).
4. Rebouche, CJ., Seim, H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu. Rev. Nutr. 18, 39–61 (1998).

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