Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes
Gerardo Calderon,
Alison McRae,
Juraj Rievaj,
Judith Davis,
Inuk Zandvakili,
Sara Linker-Nord,
Duane Burton,
Geoffrey Roberts,
Frank Reimann,
Bronislava Gedulin,
Adrian Vella,
Nicholas F LaRusso,
Michael Camilleri,
Fiona M Gribble,
Andres Acosta
Affiliations
Gerardo Calderon
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Alison McRae
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Juraj Rievaj
University of Cambridge, UK; Current affiliation: Dosage Form Design & Development, AstraZeneca Granta Park, Cambridge CB21 6GH, UK
Judith Davis
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Inuk Zandvakili
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Sara Linker-Nord
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Duane Burton
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Geoffrey Roberts
Current affiliation: Dosage Form Design & Development, AstraZeneca Granta Park, Cambridge CB21 6GH, UK
Frank Reimann
University of Cambridge, UK
Bronislava Gedulin
Satiogen Pharmaceuticals, San Diego, CA, United States
Adrian Vella
Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
Nicholas F LaRusso
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Michael Camilleri
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States
Fiona M Gribble
University of Cambridge, UK
Andres Acosta
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton 8-142, 200 First St. S.W., Rochester, MN 55905, United States; Corresponding author.
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, randomised, 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. Findings: 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 faecal BA was associated with weight loss and with decreased fructosamine. Interpretations: In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. Funding: Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). 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.
