title: 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.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, MCN CC2308, Nashville, Tennessee 37232-2730, USA.
authors.forename: Charles Robb
authors.initials: CR
authors.lastname: Flynn
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, MCN CC2308, Nashville, Tennessee 37232-2730, USA.
authors.forename: Vance L
authors.identifier: http://orcid.org/0000-0002-5267-8951
authors.initials: VL
authors.lastname: Albaugh
authors.affiliation: Rosalind Franklin University, North Chicago, Illinois 60064, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, MCN CC2308, Nashville, Tennessee 37232-2730, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Cheung-Flynn
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, MCN CC2308, Nashville, Tennessee 37232-2730, USA.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Williams
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235-1634, USA.
authors.forename: Robert M
authors.identifier: http://orcid.org/0000-0002-0854-848X
authors.initials: RM
authors.lastname: Brucker
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235-1634, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee 37232-2561, USA.
authors.forename: Seth R
authors.initials: SR
authors.lastname: Bordenstein
authors.affiliation: Center for Quantitative Sciences, Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232-6848, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6303, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, MCN CC2308, Nashville, Tennessee 37232-2730, USA.
authors.forename: Naji N
authors.initials: NN
authors.lastname: Abumrad
mesh_terms: D000220:Adaptation, Biological; D000714:Anastomosis, Surgical / Q000379:methods*; D000818:Animals; D050110:Bariatric Surgery / Q000379:methods*; D001647:Bile Acids and Salts / Q000097:blood; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005704:Gallbladder / Q000601:surgery*; D000069196:Gastrointestinal Microbiome; D007421:Intestine, Small / Q000601:surgery*; D008099:Liver / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000601:surgery*; D011897:Random Allocation
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; C037643:bile acid binding proteins; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors