Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery

Abstract

Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity (DIO) mouse model and compare metabolic remission when bile flow is diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We find that only bile diversion to the ileum results in physiologic changes similar to RYGB, including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression. Circulating free fatty acids and triglycerides decrease while bile acids increase, particularly conjugated tauro-β-muricholic acid, an FXR antagonist. Activity of the hepatic FXR/FGF15 signalling axis is reduced and associated with altered gut microbiota. Thus bile diversion, independent of surgical rearrangement of the gastrointestinal tract, imparts significant weight loss accompanied by improved glucose and lipid homeostasis that are hallmarks of RYGB.

Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice

“…1, A and B). A DIO mouse model was induced by feeding C57BL/6 male mice an HFD (60% kcal fat) for 10 -12 wk until body weight reached Ն35 g. Following BD surgery, DIO mice lost 20% of body weight in the first 2 wk and stabilized in weight by 3 wk [in contrast to 40% weight loss that stabilized after 4 wk in the gallbladder-distal ileal anastomosis model (16)], compared with mice that were fed an LFD (Fig. 2, A and B).…”

Obesity diabetes and the role of bile acids in metabolism

“…This is in keeping with the results of bile diversion to the distal small intestine, which also results in improved weight loss, glucose tolerance, and hepatic steatosis through a 10-fold increase in bile acids. The FGF15 expression was decreased [35] . Gastric bypass operations reduced FOXO1 in the liver in diabetic rats but also in the pancreatic B cell, raising the possibility that this regulator in the pancreas may also be in part a cause of the improvement in glucose tolerance [65,66] .…”

“…On the other hand, microbiota convert primary bile acids into secondary bile acids, and it is the secondary bile acids that downregulate FXR most effectively [34] . This effect may, at least in part, modify the beneficial effect of bile acids on glucose and lipid metabolism in subjects who have had a Roux en Y operation and have developed an infected blind loop, and therefore, de-conjugation of bile salts higher up in the small bowel rather than in the colon [35] .…”

“…An interesting recent paper investigates the role of bile acids in metabolic control in obese mouse model [35] . The study examined Roux en Y gastric bypass compared to diverting bile acids to either the jejunum or ileum on weight, adiposity, glucose homeostasis, and liver metabolism.…”

Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders

“…Manipulations of the bile acid pool size by bile acid supplementation, bile acid sequestrants, or pharmacological activation of FXR and TGR5 signaling have been shown to improve insulin sensitivity and glucose tolerance in mouse models of diabetes and obesity and in nonalcoholic steatohepatitis patients (11)(12)(13). Bile acids also have been implicated in rapidly improving insulin resistance in type 2 diabetic patients after bariatric surgery and in animal models (14)(15)(16).…”