Ménage-à-trois of bariatric surgery, bile acids and the gut microbiome

Abstract

Bariatric surgeries have emerged as highly effective treatments for obesity associated type-2 diabetes mellitus. Evidently, the desired therapeutic endpoints such as rates of weight loss, lower levels of glycated hemoglobin and remission of diabetes are achieved more rapidly and last longer following bariatric surgery, as opposed to drug therapies alone. In light of these findings, it has been suspected that in addition to causing weight loss dependent glucose intolerance, bariatric surgery induces other physiological changes that contribute to the alleviation of diabetes. However, the putative post-surgical neuro-hormonal pathways that underpin the therapeutic benefits of bariatric surgery remain undefined. In a recent report, Ryan and colleagues shed new light on the potential mechanisms that determine the salutary effects of bariatric surgery in mice. The authors demonstrated that the improved glucose tolerance and weight loss in mice after vertical sleeve gastrectomy (VSG) surgery were likely to be caused by post-surgical changes in circulating bile acids and farnesoid-X receptor (FXR) signaling, both of which were also mechanistically linked to changes in the microbial ecology of the gut. The authors arrived at this conclusion from a comparison of genome-wide, metabolic consequences of VSG surgery in obese wild type (WT) and FXR knockout mice. Gene expression in the distal small intestines of WT and FXR knockout mice revealed that the pathways regulating bile acid composition, nutrient metabolism and anti-oxidant defense were differentially altered by VSG surgery in WT and FXR^-/- mice. Based on these data Ryan et al, hypothesized that bile acid homeostasis and FXR signaling were mechanistically linked to the gut microbiota that played a role in modulating post-surgical changes in total body mass and glucose tolerance. The authors’ data provide a plausible explanation for putative weight loss-independent benefits of bariatric surgery and its relationship with metabolism of bile acids.

Keywords: Vertical sleeve gastrectomy, Bile acids, Farnesoid-X-receptor, Type-2 diabetes mellitus, Gut microbiome, Bariatric surgery

Core tip: The report of Ryan et al, raises a number of questions with regard to the prevailing notion that mechanical restriction of the stomach and weight loss are the sole mechanisms that mediate the therapeutic effects of bariatric surgery. The authors showed that both lowering of body mass index and improved glucose tolerance after vertical sleeve gastrectomy (VSG) surgery were mechanistically linked to an altered composition of circulating bile acids and their ability to modulate farnesoid-X receptor (FXR) mediated signaling mechanisms. Additionally, it was observed that the wild type and FXR knockout mice, after receiving VSG surgery, were significantly different with respect to the make up of their gut microbiomes. Finally, the experiments revealed that the composition of gut microbiota in wild type VSG and FXR^-/- VSG mice were highly correlated with their differential abilities to lose weight and acquire glucose tolerance.