Ileo-Colonic Delivery of Conjugated Bile Acids Improves Glucose Homeostasis <i>via</i> Colonic GLP-1-Producing Enteroendocrine Cells in Human Obesity and Diabetes

Abstract

Background: The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. Methods: We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomized, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. Results: Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in fecal BA was associated with weight loss and with decreased fructosamine. Conclusions: In humans, BA signaling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. Trial Registration: ClinicalTrials.gov number, NCT02871882, NCT02033875. Funding Statement: Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). The study was conducted in the clinical research unit (supported by Mayo Clinic Center for Clinical and Translational Science [CCaTS] grant UL1- TR000135). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology. Declaration of Interests: AA is a stockholder in Gila Therapeutics, Phenomix Sciences and Lipiquester; he serves as a consultant for Rhythm Pharmaceuticals, General Mills, Gila Therapeutics. MC is a stockholder in Phenomix Sciences and serves as a consultant to Takeda, Allergan, Rhythm, Salix, Arena, Enterin. BG is a stockholder in Satiogen Pharmaceuticals. All other authors report no relevant financial or personal conflicts of interest. Ethics Approval Statement: Surgical specimens of fresh human colon were obtained from Tissue Bank at Addenbrooke's Hospital (Cambridge, UK) and used for experiments approved by the Research Ethics Committee. The study was approved by the Mayo Clinic Institutional Review Board, and all participants gave written informed consent.