Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome

Abstract

Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission.

Keywords: Bariatric surgery; Bile acids; Gut microbiota; RXR; Roux-en-Y gastric bypasses; TGR-5; Type-2 diabetes.

Figure 1

Anatomical changes in gastrointestinal tract resulting from: sleeve gastrectomy (A), Roux-en-Y gastric bypass - distal/scopinarized (B), Roux en Y gastric bypass - long limb (C).

Figure 2

Course and regulation of reactions catalyzed by cholesterol 7α-hydroxylase - the rate limiting enzyme in bile acid biosynthesis. Bile acids (BAs) formed from 7α-hydroxycholesterol bind to farnezoid X receptor (FXR) and inhibit expression of the gene coding for 7α-hydroxylase, subsequently diminishing the rate of BA biosynthesis in liver. Oxysterols formed from cholesterol bind to liver X receptor (LXR) and stimulate expression of the gene coding for 7α-hydroxylase and the subsequent conversion of cholesterol to 7α-hydroxycholesterol and to BAs.

Figure 3

Classic pathway of bile acid biosynthesis in the liver. A: Conversion of 7α-hydroxycholesterol to 5β-cholestan-3α, 7α-diol - a precursor of chenodeoxycholyl-CoA - and of 7α-hydroxycholesterol to 5β-cholestan-3α, 7α,12α-triol - a precursor of cholyl-CoA. B: Conversion of 5β-cholestan-3α, 7α, 12α-triol to cholyl-CoA. Note that the conversion of 5β-cholestan-3α,7α-diol to chenodeoxycholyl-CoA biosynthesis takes place in the same manner and it is catalyzed by the same liver enzymes (not shown).

Figure 4

Conjugation reactions of cholyl-CoA with taurine or glycine.

Figure 5

Overview of the enterohepatic circulation of bile acids. BAs: Bile acids; C-BAs: Conjugated bile acids; BSEP: Bile salt export proteins; ASBT: Bile acid transporter; I-BABP: Ileocyte bile-acid binding protein; OSTα/OSTβ: Organic solute transporters α/β; NTCP: Na⁺-taurocholate cotransport peptide.

Figure 6

Deconjugation of taurocholic acid by bile salt hydrolase. BSH: Bile salt hydrolase.

Figure 7

Potential mechanisms of bile acid mediated improvement of serum glucose concentration. A: Stimulatory effect of bile acids on FGF15/19 synthesis in intestinal cells (ileocytes). The activation of FXR in ileocytes by BAs leads to increased synthesis (via regulation of gene expression) and the release of fibroblast growth factor 15/19 (FGF 15/19) which, through the activation of the FGF-R present in hepatocyte and adipocyte membranes, regulates carbohydrate metabolism, leading to a decrease in circulating glucose concentrations. FGF 15/19 stimulates glycogen synthesis and inhibits gluconeogenesis in the liver and glucose disposal in adipose tissue. ↓: Decrease; ↑: Increase; B: Decreasing effect of BAs on circulating glucose concentration. BAs, by activating FXR, downregulate (via regulation of gene expression) liver gluconeogenesis and stimulate glycogen synthesis. BAs, by binding to FXR or to TGR-5 in pancreatic β-cells, stimulate insulin secretion. BAs, by binding to FXR or TGR-5 in adipose tissue and skeletal muscle, improve insulin sensitivity. ↓: Decrease; C: Potential mechanisms of BA-mediated decrease in circulating glucose concentrations after bariatric surgery caused by the increased release of GLP-1 by intestinal L-cells. ↓: Decrease; ↑: Increase. FXR: Farnezoid X receptor; FGR: Fibroblast growth factor; GLP: Glucagon-like peptide-1; BAs: Bile acids.

Figure 8

Bile acids as regulatory molecules and receptors activated by bile acids present in different organs.