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Cited by 567Drug Transport and Resistance MechanismsGut microbiota and healthBerberine and alkaloids research

Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism

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Pathak, Preeti, Xie, Cen, Nichols, Robert G., Ferrell, Jessica M., Boehme, Shannon, Krausz, Kristopher W., Patterson, Andrew D., Gonzalez, Frank J. +1 more·2018·Hepatology
DOI 10.1002/hep.29857PMC PMC6111007
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Abstract

Bile acids activate farnesoid X receptor (FXR) and G protein–coupled bile acid receptor‐1 (aka Takeda G protein–coupled receptor‐5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon‐like peptide‐1 (GLP‐1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine‐restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP‐1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX‐induced and lithocholic acid–producing bacteria Acetatifactor and Bacteroides . Antibiotic treatment completely reversed the FEX‐induced metabolic phenotypes and inhibited taurolithocholic acid synthesis, adipose tissue browning, and liver bile acid synthesis gene expression but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP‐1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice. Conclusion : This study uncovered a mechanism in which activation of intestinal FXR shaped the gut microbiota to activate TGR5/GLP‐1 signaling to improve hepatic glucose and insulin sensitivity and increase adipose tissue browning; the gut microbiota plays a critical role in bile acid metabolism and signaling to regulate metabolic homeostasis in health and disease. (H epatology 2018).

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  • Bacteria-mediated transformation of host bile has a notable impact on host physiology, regulating bile acid and cholesterol metabolism, host energy balance and weight gain.

    “Numerous studies have explicitly demonstrated that bacteria-mediated transformation of host bile has a notable impact on host physiology, regulating bile acid and cholesterol metabolism, host energy balance and weight gain (Hartmann et al., 2018;Pathak et al., 2018;Sayin et al., 2013;Wahlstrom et al., 2016).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Pathak et al., 2018

    The Introduction describes bacterial conversion of host bile acids, and the Discussion links the resulting bile acids to metabolic signaling, adipose browning, and reduced weight. The Discussion reports improved lipid metabolism, but the passages do not establish the more specific claim about cholesterol metabolism; the study’s findings are also in mice rather than hosts generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Bile acids can regulate host metabolism and immunity through the farnesoid X receptor (FXR), which is activated by bile acids.

    “BAs can regulate host metabolism and immunity through the farnesoid X receptor (FXR), which is activated by bile acids (Pathak et al., 2018).”

    From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Pathak et al., 2018

    The Introduction (page unavailable) says bile acids activate FXR and regulate lipid, glucose, and energy homeostasis through FXR and TGR5. It does not establish regulation of immunity through FXR; its discussion of reduced inflammation concerns TGR5 instead. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Pathak, P., Xie, C., Nichols, R. G., Ferrell, J. M., Boehme, S., Krausz, K. W., Patterson, A. D., Gonzalez, F. J., & Chiang, J. Y. L.
Affiliations
  • Northeast Ohio Medical University (US)
  • National Institutes of Health (US)
  • Pennsylvania State University (US)
Corresponding author
Chiang, John Y.L.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-05-21
Volume
68
Issue
4
Pages
1574-1588
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.29857
PMC
PMC6111007
OpenAlex
W2794373470
Cited by
567
References
5
Citations by year
2026: 69 · 2025: 78 · 2024: 66 · 2023: 75 · 2022: 77 · 2021: 75 · 2020: 63 · 2019: 44 · 2018: 20
FWCI
18.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01dk044442-26)
  • National Cancer Institute
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 58379, DK44442, R01-DK-044442, R01DK058379, R56DK044442, R37DK058379)
  • National Institute of Environmental Health Sciences (R01ES022186, ES022186)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
Keywords
farnesoid X receptor, TGR5, gut microbiota, taurolithocholic acid, FGF15, FGF21, glucagon-like peptide-1, insulin sensitivity, glucose tolerance, adipose tissue browning, bile acid metabolism, Bacteroides, antibiotic therapy, obesity, diabetes mellitus, hepatic glucose metabolism
MeSH terms
Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Disease Models, Animal, Male, Mice, Inbred C57BL, Random Allocation, Sensitivity and Specificity, Signal Transduction, Receptors, Cytoplasmic and Nuclear, GTP-Binding Proteins, Receptors, G-Protein-Coupled, Lipid Metabolism, Mice, Glucagon-Like Peptide 1

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