12 January - 20 June 2016

Gut microbiota pathways may help protect against obesity

A study conducted by researchers from the Cleveland Clinic and Wake Forest University amongst others, published in Cell Reports, indicates that altering gut microbe metabolic pathways may be able to help prevent obesity.

A study conducted by researchers from the Cleveland Clinic and Wake Forest University amongst others, published in Cell Reports, indicates that altering gut microbe metabolic pathways may be able to help prevent obesity.

The study notes that the Western diet includes several nutrients found in red and processed meats, egg yolk and liver, namely choline, carnitine and lecithin and that certain communities within the gut microbiota metabolise these to form trimethylamine (TMA). A metabolic pathway then converts TMA, using an enzyme Flavin-containing monooxygenase 3 (FMO3) to trimethylamine N-oxide (TMAO). Previous studies have shown high levels of TMAO to be linked to cardiovascular disease (CVD) and as gut microbiota has been linked to obesity, Brown et al hypothesised that “the TMAO pathway may be mechanistically linked to the pathogenesis of obesity”.

Brown et al. initially investigated the levels of TMAO in 435 patients in the Cleveland clinic undergoing evaluation for either CVD risk or fatty liver disease and found that levels of TMAO were “closely correlated” with type 2 diabetes mellitus risk. Brown et al also used data from a study of Finnish men and several cohorts of American men and women chosen for their “gender, ethnic and racial diversity” and found that FMO3 levels were positively associated with BMI and adiposity and negatively associated with insulin sensitivity.  They also investigated TMAO levels and obesity -related traits in inbred strains of mice that can be used to analyse the genetic and environmental factors underlying complex traits such as obesity and diabetes and found that again, levels of TMAO were positively associated with body weight, fat mass and adiposity.

Brown et al then performed several experiments using mice bred to inhibit their expression of FMO3. The researchers found that depletion of FM03 or genetic deletion protected mice against obesity when fed a high fat diet. They also found that even when TMAO was added to the diet directly, the FMO3-negative mice still had lower TMAO levels than the controls and that direct provision of TMAO did not “reverse the ability of FMO3 treatment to attenuate high-fat diet -induced body weight gain”. The FMO3-negative mice experiments also showed that the removal of FMO3 was associated with the increased expression of genes associated with beige or brown fat cells.  A press release on the study notes that this is important as these fat cells tend to be more metabolically active than white fat cells.

In discussion, Brown et al. suggest that identifying the mechanisms and links between “TMA, FMO3, TMAO and human health and disease will be needed to understand where to therapeutically intervene” and conclude by saying that “Given the numerous strong associations of the gut microbe-driven TMAO pathway with human disease, this work has broad implications for drug discovery efforts targeting gut microbes themselves instead of the human host in which they reside.” Brown is also quoted by MedicalXpress  as saying that “Obesity, diabetes and cardiovascular disease are strongly linked. While the microbiome has been shown to affect cardiovascular disease, there is as yet no concrete evidence of precisely how gut bacteria influence obesity. These findings shed light on a possible way to manipulate the microbiome with therapeutics to combat our obesity and diabetes epidemic”

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