Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats
Objective: The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the...
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doaj-1a10f139ef404633a669e702e42eab742021-02-11T04:20:39ZengElsevierMolecular Metabolism2212-87782021-02-0144101132Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in ratsT.M. Zaved Waise0Yu-Mi Lim1Zahra Danaei2Song-Yang Zhang3Tony K.T. Lam4Toronto General Hospital Research Institute, UHN, Toronto, CanadaToronto General Hospital Research Institute, UHN, Toronto, Canada; Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of KoreaToronto General Hospital Research Institute, UHN, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, CanadaToronto General Hospital Research Institute, UHN, Toronto, CanadaToronto General Hospital Research Institute, UHN, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada; Banting and Best Diabetes Center, University of Toronto, Toronto, Canada; Corresponding author. Toronto General Hospital Research Institute, UHN, Toronto, Canada.Objective: The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown. Methods: Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed. Results: USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum. Conclusions: We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats.http://www.sciencedirect.com/science/article/pii/S2212877820302064Small intestineNutrient sensingGlucose toleranceBile acidsFXR |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
T.M. Zaved Waise Yu-Mi Lim Zahra Danaei Song-Yang Zhang Tony K.T. Lam |
spellingShingle |
T.M. Zaved Waise Yu-Mi Lim Zahra Danaei Song-Yang Zhang Tony K.T. Lam Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats Molecular Metabolism Small intestine Nutrient sensing Glucose tolerance Bile acids FXR |
author_facet |
T.M. Zaved Waise Yu-Mi Lim Zahra Danaei Song-Yang Zhang Tony K.T. Lam |
author_sort |
T.M. Zaved Waise |
title |
Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats |
title_short |
Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats |
title_full |
Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats |
title_fullStr |
Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats |
title_full_unstemmed |
Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats |
title_sort |
small intestinal taurochenodeoxycholic acid-fxr axis alters local nutrient-sensing glucoregulatory pathways in rats |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2021-02-01 |
description |
Objective: The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown. Methods: Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed. Results: USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum. Conclusions: We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats. |
topic |
Small intestine Nutrient sensing Glucose tolerance Bile acids FXR |
url |
http://www.sciencedirect.com/science/article/pii/S2212877820302064 |
work_keys_str_mv |
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