Early Increases in Bile Acids Post Roux-en-Y Gastric Bypass Are Driven by Insulin-Sensitizing, Secondary Bile Acids

Abstract

Context: Roux-en-Y gastric bypass (RYGB) is the most effective treatment for morbid obesity and resolution of diabetes. Over the last decade, it has become well accepted that this resolution of diabetes occurs before significant weight loss; however, the mechanisms behind this effect remain unknown and could represent novel therapeutic targets for obesity and diabetes. Bile acids have been identified as putative mediators of these weight loss-independent effects.

Objective: To identify the longitudinal changes in bile acids after RYGB, which may provide mechanistic insight into the weight loss-independent effects of RYGB.

Design: Observational study before/after intervention.

Setting: Academic medical center.

Patients/participants: Samples were collected from morbidly obese patients (n = 21) before and after RYGB.

Intervention: RYGB.

Main outcome measures: Seventeen individual bile acid species were measured preoperatively and at 1, 6, 12, and 24 months postoperatively. Anthropometric, hormonal, and hyperinsulinemic-euglycemic clamp data were also examined to identify physiological parameters associated with bile acid changes.

Results: Fasting total plasma bile acids increased after RYGB; however, increases were bimodal and were observed only at 1 (P < .05) and 24 months (P < .01). One-month increases were secondary to surges in ursodeoxycholic acid and its glycine and taurine conjugates, bacterially derived bile acids with putative insulin-sensitizing effects. Increases at 24 months were due to gradual rises in primary unconjugated bile acids as well as deoxycholic acid and its glycine conjugate. Plasma bile acid changes were not significantly associated with any anthropometric or hormonal measures, although hepatic insulin sensitivity was significantly improved at 1 month.

Conclusions: Overall findings suggest that bacterially derived bile acids may mediate the early improvements at 1 month after RYGB. Future studies should examine the changes in specific bile acid chemical species after bariatric procedures and bile acid-specific signaling changes.

Figure 1.

Plasma concentrations of total, UDCA, and conjugated UDCA species preoperatively and after RYGB. Serial plasma samples were collected for bile acid measurements. A, Total bile acid concentration, which represents the sum of 17 different bile acid species, are significantly increased at 1 and 24 months after RYGB. B—D, Increases in total bile acid concentrations seen at 1 month are due to increases in UDCA (B), GUDCA (C), and TUDCA (D). Sample size for each time point in the surgical cohort is 19 to 21 individuals. Lean individuals (n = 8) are included for visual comparison only. Asterisks represent significant differences of indicated time points: *, P < .05; **, P < .01; ***, P < .001, using mixed-effects modeling with Bonferroni corrections for pairwise comparisons.

Figure 2.

Plasma concentrations of selected primary and secondary bile acid concentrations preoperatively and after RYGB. Serial plasma samples were collected for bile acid measurements preoperatively and at 1, 6, 12, and 24 months postoperatively. A—D, CA (A) and CDCA (B) have increases observed at 24 months, whereas DCA (C) and its glycoconjugate GDCA (D) have gradual increases at 12 and 24 months compared to preoperative levels, respectively. E, Hyocholic acid (HCA) had a small but significant increase at 24 months compared to preoperative levels. Sample size for each time point in the surgical cohort is 20 or 21 individuals. Lean individuals (n = 8) are included for visual comparison only. Asterisks represent significant differences of indicated time points: *, P < .05; **, P < .01, using mixed-effects modeling with Bonferroni corrections for pairwise comparisons.

Figure 3.

Circulating FGF19 concentrations preoperatively and after RYGB. Serial plasma samples were analyzed for FGF19 concentrations preoperatively and at 1, 6, 12, and 24 months postoperatively. Sample size for each time point in the surgical cohort is 20 or 21 individuals. Lean individuals (n = 8) are included for visual comparison only. Asterisks represent significant differences of indicated time points compared to preoperative levels: **, P < .01, using mixed-effects modeling with Bonferroni corrections for pairwise comparisons.