post The role of short-chain fatty acids in driving obesity Should we blame acetate w

In a recent paper by Perry et al., researchers describe an investigation into the putative mechanisms by which gut microbiota alterations may lead to obesity, insulin resistance, and metabolic syndrome. Authors describe increased production of acetate by altered gut microbiota in rats. They link this to activation of the parasympathetic nervous system, increased glucose-stimulated insulin secretion, higher ghrelin secretion, hyperphagia, and obesity. Thus, they point to increased acetate production as a driver of metabolic syndrome.

Those in the field have known for decades that microbes produces acetate (see here, for example) and that this acetate may contribute to changes in liver lipid metabolism as well as glucose metabolism and food intake. Thus, it is well known that chronically increasing acetate abundance can drive lipogenesis. A link between acetate and diabetes has been also shown in the past, although it is still debated.

The association between microbes and neuronal routes, in addition, has been well described: for example, here.

The key contribution of this paper by Perry et al. is the discovery that in vivo turnover of acetate is specifically influenced by the gut. In addition, they used a collection of interesting and sophisticated tools to demonstrate that acetate can directly increase glucose-stimulated insulin release, affecting both the gut-brain axis and peripheral sites.

Attributing all of the observed effects to changes in acetate, however, is likely premature. Among the short-chain fatty acids (SCFAs), acetate is probably the most debated in terms of its beneficial or detrimental metabolic effects.

In the paper by Perry, et al., authors did not discuss another key body of work showing that prebiotic fermentation by the gut microbiota can increase the abundance of SCFAs, including (in some studies) the overall pool of SCFAs. For example, it has been shown that acetate is increased with prebiotic fructooligosaccharides (FOS) (see here), and that this is associated with reduced body weight and fat mass, decreased diabetes, and a lower food intake. Another  related paper by Gary Frost and colleagues showed that prebiotics such as inulin (C13 labeled) increased acetate that reached the brains of rats and reduced ghrelin production, leading to a reduction in food intake, body weight, and fat mass through mechanisms involving neuronal activity. The effects of acetate in this context, therefore, seem to be contrary to those in the current study Perry and colleagues.

Another complexity not explored in the Perry, et al. work is that the microbiota rapidly transform acetate into other SCFAs. The 10 days of intragastric infusion of SCFA probably changed both the microbiota and the overall SCFA profile in the gut. Ratios of SCFAs are also important to consider: if the ratio of acetate to propionate is changed, for example, the real abundance of acetate can be increased. So here it remains unclear whether the observed effects are attributable to the acetate itself or to products of the cross-feeding.

A key question about these mechanisms is what drives the secretion of specific hormones. The authors used a protocol of acetate administration for 10 days, and the intragastric route means it would be rapidly absorbed—but this may also change hormonal routes. Thus, the question of whether changes in secretion of specific hormones is due to luminal mechanisms (in the intestine/stomach) or blood-driven mechanisms is not yet resolved.

In the Perry, et al. study, acetate probably did strongly contribute to the changes observed in the rodents, but unfortunately the authors did not put their findings into the general picture of the important literature showing that fermentation of specific dietary fibres may have an impact on SCFAs (including acetate) and on metabolism. As an ultimate example, the recent paper by De Vadder et al. elegantly shows that, in response to dietary fibres, another product of microbiota fermentation (succinate) can be a precursor of glucose production in the gut but can improve glucose homeostasis by a mechanism depending on intestinal neoglucogenesis.

Thus, addressing the central idea of the Perry, et al. paper when it comes to humans, acetate may or may not be the driver of obesity; most likely, it is dependent on the microbiota and the dietary fibres used (e.g. resistant starches, prebiotics). Overall, it seems the story of how the gut microbiota drive obesity is not yet complete.

References:

Frost G, Sleeth ML, Sahuri-Arisoylu M. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nature Communications. 2014;5 doi:10.1038/ncomms4611

Perry RJ, Peng L, Barry NA. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature. 2016;534(213-217). doi:10.1038/nature18309

Patrice D. Cani
Patrice D. Cani
Professor Patrice D. Cani is researcher from the Belgian Fund for Scientific Research (FRS-FNRS), group leader in the Metabolism and Nutrition research group at the Louvain Drug Research Institute (LDRI) from the Université catholique de Louvain (UCL), Brussels, Belgium, and WELBIO (Walloon Excellence in Lifesciences and BIOtechnology) investigator. He is currently member of several international associations, he is member of the Alumni College from the Royal Belgian Academy of Sciences, and he has been elected in the board of directors of the LDRI (UCL). Patrice D. Cani has a M.Sc. in Nutrition and another M.Sc. in health Sciences, he is registered dietitian and PhD in Biomedical Sciences. His main research interests are the investigation of the role of the gut microbiota in the development of metabolic disorders, such as obesity, type 2 diabetes and low grade inflammation. More specifically, he is investigating the interactions between the gut microbiota, the host and specific biological systems such as the endocannabinoid system and the innate immune system in the context of obesity, type 2 diabetes and metabolic inflammation. Prof Cani is author and co-author of more than 110 scientific research papers published in peer-reviewed international journals, conferences and book chapters.