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Cited by 84Gut microbiota and healthDiabetes Treatment and ManagementDrug Transport and Resistance Mechanisms

The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids

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Ducastel, Sarah, Touche, Véronique, Trabelsi, Mohamed-Sami, Boulinguiez, Alexis, Butruille, Laura, Nawrot, Margaux, Peschard, Simon, Chávez-Talavera, Oscar +12 more·2020·Scientific Reports
DOI 10.1038/s41598-019-56743-xPMC PMC6957696
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Abstract

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.

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  • There is increasing evidence from animal studies and clinical trials to suggest that GLP-1 receptor agonists could be beneficial in the treatment of PD.

    “There is increasing evidence from animal studies and clinical trials to suggest that GLP-1 receptor agonists could be beneficial in the treatment of PD, and one study using a prebiotic supplement that enhanced SCFA levels showed an increase GLP-1 levels in mouse models [141–144].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [144]

    The Discussion and Results (Figure 5; page numbers not supplied) report increased active GLP-1 after prebiotic ITF supplementation in FXR-deficient mice; the Discussion says ITF is known to increase local SCFA production. These passages support the mouse prebiotic finding, but they do not address Parkinson’s disease (PD), clinical trials, or whether GLP-1 receptor agonists benefit PD. (LLM, conf=0.88)

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  • One study using a prebiotic supplement that enhanced SCFA levels showed an increase GLP-1 levels in mouse models.

    “There is increasing evidence from animal studies and clinical trials to suggest that GLP-1 receptor agonists could be beneficial in the treatment of PD, and one study using a prebiotic supplement that enhanced SCFA levels showed an increase GLP-1 levels in mouse models [141–144].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [144]

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Authors
Ducastel, S., Touche, V., Trabelsi, M.-S., Boulinguiez, A., Butruille, L., Nawrot, M., Peschard, S., Chávez-Talavera, O., Dorchies, E., Vallez, E., Annicotte, J.-S., Lancel, S., Briand, O., Bantubungi, K., Caron, S., Bindels, L. B., Delzenne, N. M., Tailleux, A., Staels, B., & Lestavel, S.
Affiliations
  • Inserm (FR)
  • Centre National de la Recherche Scientifique (FR)
  • UCLouvain (BE)
Corresponding author
Staels, Bart
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-01-13
Volume
10
Issue
1
Pages
174-174
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-56743-x
PMC
PMC6957696
OpenAlex
W3000671553
Cited by
84
References
4
Citations by year
2026: 13 · 2025: 13 · 2024: 9 · 2023: 9 · 2022: 20 · 2021: 12 · 2020: 7
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Digital Access to Libraries (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
Funders
  • Ministère de l'Enseignement Supèrieur et de la Recherche (PhD fellowship)
  • Agence Nationale de la Recherche (ANR-FXREn)
  • European Genomic Institute for Diabetes (E.G.I.D., ANR-10-LABX-46)
  • European Research Council (694717)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
farnesoid X receptor, glucagon-like peptide-1 secretion, short-chain fatty acids, gut microbiota, FFAR2, FFAR3, enteroendocrine L cells, Gαq signaling, prebiotic supplementation, bile acid sequestrants, type 2 diabetes, colonic biopsy, colonoids
MeSH terms
Receptor, Farnesoid X-Activated, Animals, Colon, Fatty Acids, Volatile, Male, Mice, Inbred C57BL, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Receptors, G-Protein-Coupled, Mice, Glucagon-Like Peptide 1, Microbiota

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