Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes
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...
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Elsevier
2020-05-01
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Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420301341 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes EBioMedicine |
author_facet |
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 |
author_sort |
Gerardo Calderon |
title |
Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes |
title_short |
Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes |
title_full |
Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes |
title_fullStr |
Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes |
title_full_unstemmed |
Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes |
title_sort |
ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic glp-1-producing enteroendocrine cells in human obesity and diabetes |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2020-05-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2352396420301341 |
work_keys_str_mv |
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doaj-81f621a9ddf64e54b9db7c70d00bcc3d2020-11-25T03:20:49ZengElsevierEBioMedicine2352-39642020-05-0155Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetesGerardo Calderon0Alison McRae1Juraj Rievaj2Judith Davis3Inuk Zandvakili4Sara Linker-Nord5Duane Burton6Geoffrey Roberts7Frank Reimann8Bronislava Gedulin9Adrian Vella10Nicholas F LaRusso11Michael Camilleri12Fiona M Gribble13Andres Acosta14Clinical 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 StatesClinical 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 StatesUniversity of Cambridge, UK; Current affiliation: Dosage Form Design & Development, AstraZeneca Granta Park, Cambridge CB21 6GH, UKClinical 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 StatesClinical 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 StatesClinical 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 StatesClinical 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 StatesCurrent affiliation: Dosage Form Design & Development, AstraZeneca Granta Park, Cambridge CB21 6GH, UKUniversity of Cambridge, UKSatiogen Pharmaceuticals, San Diego, CA, United StatesDivision of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, MN, United StatesClinical 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 StatesClinical 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 StatesUniversity of Cambridge, UKClinical 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.http://www.sciencedirect.com/science/article/pii/S2352396420301341 |