The Role of Gut Adaptation in the Potent Effects of Multiple Bariatric Surgeries on Obesity and Diabetes

Abstract

Summary Bariatric surgical procedures such as vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most potent treatments available to produce sustained reductions in body weight and improvements in glucose regulation. While traditionally these effects are attributed to mechanical aspects of these procedures such as restriction and malabsorption, a growing body of evidence from mouse models of these procedures points to physiological changes that mediate the potent effects of these surgeries. In particular, there are similar changes in gut hormone secretion, bile acid levels and composition after both of these procedures. Moreover, loss-of-function of the nuclear bile acid receptor (FXR) greatly diminishes the effects of VSG. Both VSG and RYGB are linked to profound changes in the gut microbiome that also mediate at least some of these surgical effects. We hypothesize that surgical rearrangement of the gastrointestinal tract results in enteroplasticity caused by the high rate of nutrient presentation and altered pH in the small intestine that contribute to these physiological effects. Identifying the molecular underpinnings of these procedures provides new opportunities to understand the relationship of the gastrointestinal tract to obesity and diabetes as well as new therapeutic strategies to harness the effectiveness of surgery with less invasive approaches.

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Although treatment with SCFAs is not feasible, as they are very unpalatable and do not reach the distal small and large intestine where they are endogenously produced, prebiotic treatment (nondigestible fibre) effectively increases distal intestinal SCFA production and improves glucose homeostasis in rodents (Cani et al 2006b, Everard et al 2011, which is thought to be mediated through an increase in gut peptide release (Cani et al 2004, 2006b, Everard et al 2011, Neyrinck et al 2012. While some evidence exists for the beneficial effects of fermentable dietary fibre in humans (Archer et al 2004, Cani et al 2006a, Parnell & Reimer 2009), intake of dietary fibre is generally low (Howarth et al 2003), and prebiotic treatment may not readily increase propionate production (Chambers et al 2015). As such, a novel carrier molecule was developed to selectively increase colonic propionate levels.…”

“…For example, in the RYGB microbiota transplant study described above, levels of propionate were increased in both the RYGB-treated donor and the recipient mice (Liou et al 2013). Indeed, supplementation with propionate or fermentable fibre is known to reduce appetite and improve glucose tolerance, possibly from inducing distal intestinal gut peptide secretion 230:3 (Everard et al 2011, Lin et al 2012, Chambers et al 2015, Psichas et al 2015b. Ileal propionate activates mucosal FFAR2 to lower hepatic glucose production through a GLP-1-dependent neuronal pathway (Zadeh-Tahmasebi et al 2016), while increased concentrations of SCFA in the large intestine have been shown to increase circulating levels of GLP-1 and PYY and reduce postprandial insulin and glucose levels (Tolhurst et al 2012, Psichas et al 2015b).…”

“…As such, a novel carrier molecule was developed to selectively increase colonic propionate levels. Treatment with this inulin-propionate ester for 24 weeks reduced weight gain and adipose distribution, and prevented the decrease in glucose tolerance and insulin sensitivity exhibited by the control group (Chambers et al 2015). In addition, faecal microbiota transfer (FMT) represents another potential mechanism to increase SCFA levels and improve glucose homeostasis, as duodenal transfer of microbiota from lean humans into those with metabolic syndrome results in an increase in butyrate-producing bacteria and insulin sensitivity 6 weeks after the transfer (Vrieze et al 2012).…”

“…In addition to distal intestinal nutrient sensing and gut peptide changes, rearranging the intestinal tract during bariatric surgery profoundly alters bile acid levels and composition, which has been suggested as key contributor to its success (Seeley et al 2015). Bile acids have been implicated in the regulation of glucose homeostasis through their effects on glucose production and glucoseinduced insulin secretion (Thomas et al 2008(Thomas et al , 2009).…”

Is Bariatric Surgery an Effective Treatment for Type II Diabetic Kidney Disease?

“…A growing body of research now finds this perspective to be outdated. Ongoing investigations are now beginning to piece together a much more complex picture that involves postsurgical changes leading to adaptations in the gut that are modulated by its own hormonal and nervous systems interacting with gut microbia, bile acids, and nutrient delivery (23).…”