The prevalence of obesity has increased at a breathtaking rate over the last few decades, with nearly half of the global population estimated to be overweight. This staggering ratio represents a tremendous disease burden since obesity is a major risk factor for many comorbidities, such as cardiovascular disease, fatty liver, and type 2 diabetes. Challenging solutions to address the rise in obesity are complex and not readily isolated to a small collection of genes.

For solutions, think small?

Starting with pioneering work by Peter Turnbaugh Ph.D., and Jeffrey I. Gordon, M.D., awareness into the gut microbiome became an area of interest. The team uncovered that obesity was transmissible to lean mice by transplanting a microbiome derived from obese mice. Subsequently, the last decade of research has shown that an imbalance in the tiny microbes that live in us – the collective gut microbiome - is a factor in obesity and related disorders.

The association of the microbiome with obesity has produced some prevailing patterns such as a reduction in diversity and richness of the gut microbiome in obese patients, but the literature lacks a clear consensus on the species that drive obesity. Hence, although there is a clear association with microbiome imbalance and obesity, actionable insights have been lacking.

Enter something even smaller to define the microbiome’s role in obesity - metabolites

The functional expression of the microbiome is frequently mediated by something even smaller than the microbes –metabolites. From brain disorders to immune function, to our circadian clock, the microbiome heavily influences these traits through metabolites. In obesity and associated diseases, some of the most actionable insights are emerging through deeply exploring metabolites with metabolomics. These insights started with seminal work showing that trimethylamine N-oxide (TMAO) contributes to cardiovascular disease and, upon blocking its production, atherosclerosis can be reduced.

Other recent work echoes that using metabolomics to survey metabolites is a key to uncovering actionable insights into how the microbiome impacts obesity and its associated diseases.

For example, research published in Nature by scientists at the Weizmann Institute showed that the gut microbiome has a significant part in yo-yo weight loss and regain. Even after obese mice lose weight, the microbiome and its associated metabolites remain changed for an extended period. These changes “poise” mice to rapidly regain weight when they resume a poor diet. Thus, one bout of obesity restructures the microbiome in a way that predisposes one to weight gain.

Although many bacterial species (i.e., OTUs) were persistently changed after obesity, a strategy for resisting the weight regain was illuminated with the Metabolon, Inc. platform. Metabolomics showed that flavonoids were consistently reduced after obesity.  Supplementing the diet with these flavonoids increased energy expenditure and allowed mice to resist weight regain. This approach (i.e., post-biotic) provides a potential avenue for combatting the effects of the yo-yo diet.

Other recent work published in Cell by Ara Koh and colleagues at the University of Gothenburg used Metabolon’s platform to show that a single metabolite produced by gut microbes - imidazole propionate - is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling. This finding suggests that this single chemical entity from microbes may contribute to the development of type 2 diabetes. 

Collectively, the results show that interrogating the tiny functional end of the relationship between the host and the microbiome – metabolites – will continue to be a critical approach to assembling this complex puzzle of obesity to ultimately develop strategies to counteract its rapid worldwide rise.

References:

Turnbaugh, Peter J., et al. (2006). "An obesity-associated gut microbiome with increased capacity for energy harvest." Nature 444.7122: 1027.

Wang, Zeneng, et al. (2011). "Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease." Nature 472.7341: 57.

Thaiss, Christoph A., et al. (2016). "Persistent microbiome alterations modulate the rate of post-dieting weight regain." Nature 540.7634: 544.

Koh, Ara, et al. (2018) "Microbially produced imidazole propionate impairs insulin signaling through mTORC1." Cell 175.4: 947-961.