Are Bile Acids the New Gut Hormones? Lessons From Weight Loss Surgery Models

Abstract

Bileacidsareincreasinglyrecognizedasmoleculeswith endocrine functions (1), but their effect on gut hormones, energy expenditure, and insulin sensitivity has not been fully elucidated. Bile acids do represent an attractive target for obesity and type 2 diabetes from a therapeutic pointofviewbecauseoftheendogenouschangesobserved after gastric bypass (2). The anatomical changes with alteredbileflowaftergastricbypasssurgerymakestudieson animal models such as the one by Kohli et al (2) extremely relevant.Gastricbypasssurgeryhasbeenshowntobesafe and effective for inducing weight loss and ameliorating hyperglycemia, but understanding the mechanism of action and dissecting the role of bile acid manipulation in particular, not only offers important insight into glucose metabolism, but also may open the door for even more effectivetreatmentoptionsfortype2diabetesandobesity. These therapies could be medical, surgical, endoscopic, and perhaps more importantly combinational therapy. ThestudybyKohlietal(2)demonstratesthemetabolic effect of diverting bile to the distal gut. The authors used aninnovativeapproachbyplacingacatheterintothecommon bile duct of male obese rats to drain bile to the more distal jejunum. Bile diversion was associated with increased serum bile acids, enhanced postprandial glucagon-like peptide-1 response, improved glucose tolerance, and reduced hepatic steatosis. None of these effects were observed in the appropriate sham group. By isolating the effect of the altered bile flow without changing the length of the gut and the size of the stomach, this work suggests that the metabolic effects of gastric bypass cannot be explained by weight loss alone. Consistent with the work of Kohlietal(2)inanotherratmodel,itwasalsoshownthat drainage of endogenous bile into the terminal ileum was associated with an enhanced satiety gut hormone response, reduced food intake, and lower body weight (3). Kohli et al advanced our current knowledge by demonstrating that manipulating bile flow without altering the anatomy of the small bowel leads to improved glucose tolerance. During the last decade, the role of gut hormones after gastric bypass surgery has featured prominently (4), but it hasalsobecomeevidentthatguthormonesdonotexplain alltheeffectsseenafterweightlosssurgery.Forone,when gut hormones are blocked with a somatostatin analog, a substantial increase in ad libitum food intake is observed, but food intake does not return to presurgical levels (5). Second,manyofthebeneficialchangesinglycemiccontrol occur even after open gastric bypass surgery (6), which is associated with increased inflammation and should have