Prof Juan Carlos Kaski, St George's, University of London, UK

Research in recent years has shown that intestinal microbial organisms, collectively named ‘microbiota’, take part in the metabolism of their host. (1)

Moreover, it has become apparent that the microbiota may play an important role in the development of metabolic syndrome and diabetes. Changes to lifestyle and an increased availability of energy-rich foods, are responsible for the worldwide obesity epidemic. Importantly, the gut microbiota can also have an influence on metabolic processes, such as energy extraction from food, and it has been suggested to represent “an environmental factor that contributes to obesity and its comorbidities (such as insulin resistance, diabetes and cardiovascular disease)” (2).  For example, a gastric bypass contributes substantially to weight reduction and also lowers the risk of diabetes and cardiovascular disease in obese subjects. (3,4) These observations have shed light onto the relationship between the gut microbiota and obesity. After a gastric bypass, diabetes can resolve before patients begin to lose weight, suggesting that this type of surgical intervention may have a direct “antidiabetic” effect. The mechanisms responsible for this association are not very well known at this point in time but a shift in the composition of the faecal microbiota of humans (5) has been suggested to contribute to the improved metabolic phenotype after a gastric bypass.

Studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, termed trimethylamine-N-oxide (TMAO). A recent study by Tang et al (1) assessed the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in human subjects. They quantified plasma and urinary levels of TMAO and plasma choline and betaine levels (liquid chromatography and online tandem mass spectrometry) after a phosphatidylcholine challenge, i.e. ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine in healthy volunteers before and after the administration of oral antibiotics, which eliminated the gut flora. They also assessed the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events such as death, myocardial infarction and stroke during 3 years of follow-up in 4007 patients undergoing elective diagnostic coronary angiography.

The main results of the study were: 1. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after the withdrawal of antibiotics.

  1. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (P<0.001).
  2. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001).

Thus the production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota and increased TMAO levels appear to predict an increased risk of major adverse cardiovascular events.

Certainly a new and promising field of research has now been opened as a result of data indicating that the gut microbiota may be a therapeutic target for metabolic diseases. Several avenues of research are being currently pursued such as supplementing the diet with non- digestible food ingredients, or probiotics that stimulate the expansion of specific components of the gut microbiota to improve metabolic pathways. Probiotics are certainly of interest as a suitable rational approach for the prevention of obesity and other metabolic conditions. Studies, however, are required and these have to be placebo-controlled studies with sufficient power to answer these important research questions.


  1. Tang WHW et al. N Engl J Med 2013; 368:1575-84. DOI: 10.1056/NEJMoa1109400
  2. Tremaroli V and Bäckhed F. Review – Nature 2012; 489:212-219
  3. Sjostrom, L. et al. Engl. J. Med 2004; 351: 2683–2693.
  4. Sjostrom, L. et al. N. Engl. J. Med. 2007; 357: 741–752.
  5. Zhang, H. et al. Proc. Natl Acad. Sci. USA 2009; 106: 2365–2370.
Cardio Debate Expert Comments

There are two broad approaches to studying the role of the gut microbiota (GM) in treating and preventing cardio-metabolic diseases: either the GM can be changed or specific effects on host physiology can be targeted. The study discussed (1) is an elegant example of the exploration of the latter suggesting a way that quite specific dietary change could reduce risk of cardiovascular disease.

The finding of the association of plasma levels of TMAO with risk of cardiovascular events is of interest but must be viewed with caution. Although the effect was significant the marked attenuation after controlling for conventional risk factors suggests that there may be residual confounding explaining the association (1). This does not detract from the important observation suggesting that restricting choline in the diet could reduce risk of cardiometabolic disease.

We are currently at the dawn of the study of the effect of the GM on metabolism, the immune system, cardiovascular and even psychological illness. The GM as well as being able to affect the metabolism of proatherogenic substrates can directly invade the circulatory system producing endotoxaemia. The GM can also modulate inflammatory activity through effects on fatty acid metabolism and on gut hormone receptors amongst others, and insulin sensitivity through inflammatory and metabolic mechanisms (2).

More studies of this type seeking other intermediate markers of the effect of gut microbiota on host physiology and cardiometabolic disease are called for as well as detailed studies of the human gut microbiome and metabolome (the metabolic profile of the gut microbiome as a whole) in relation to disease states and outcomes and the effect of dietary change (3,4).


  1. Tang WHW et al. N Engl J Med 2013; 368:1575-84.
  2. Claire L et al Genome Med. 2016; 8: 42.
  3. Caleb J. Kelly et al, Nutr Clin Pract. 2012 April ; 27(2): 215–225
  4. Lawrence A et al. David Nature. 2014 January 23; 505(7484): 559–563