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FXR-Dependent Modulation of the Human Small Intestinal Microbiome by the Bile Acid Derivative Obeticholic Acid
Open accessAbstract
Background & Aims: Intestinal bacteria can modify the composition of bile acids and bile acids, which are regulated by the farnesoid X receptor (FXR), affect the survival and growth of gut bacteria. We studied the effects of obeticholic acid (OCA), a bile acid analog and FXR agonist, on the intestinal microbiomes of humans and mice. Methods: We performed a phase 1 study in 24 healthy volunteers given OCA (5 mg, 10 mg, or 25 mg per day, for 17 days). Fecal and plasma specimens were collected at baseline (day 0) and on days 17 (end of dosing) and 37 (end of study). The fecal specimens were analyzed by shotgun metagenomic sequencing. A Uniref90 high stringency genomic analysis was used to assign specific genes to the taxonomic signature of bacteria whose abundance was associated with OCA. Male C57BL/6 mice were gavaged daily with water, vehicle, or OCA (10 mg/kg) for 2 weeks. Small intestine luminal contents were collected by flushing with saline and fecal pellets were collected at baseline and day 14. Mouse samples were analyzed by 16S tagged sequencing. Culture experiments were performed to determine taxonomic-specific effects of bile acids and OCA on bacterial growth. Results: Suppression of endogenous bile acid synthesis by OCA in subjects led to a reversible induction of Gram-positive bacteria that are found in the small intestine and are components of diet and the oral microbiota. We found that bile acids reduced proliferation of these bacteria in minimum inhibitory concentration assays. In these organisms, there was an increase in the representation of microbial genomic pathways involved in DNA synthesis and amino acid metabolism with OCA treatment of subjects. Consistent with these findings, mice fed OCA had reduced endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine, compared to mice fed water or vehicle. Conclusions: In studying the effects of OCA in humans and mice, we found evidence for interactions between bile acids and features of the small intestinal microbiome. These findings indicate that FXR activation alters the intestinal microbiota and could provide opportunities for microbiome biomarker discovery or new approaches to engineering the human microbiome. Clinical trial information: ClinicalTrials.gov no: NCT01933503.
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“In recent years, it has been found that there is an important bidirectional relationship between intestinal microbiota and bile acids.”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [204]
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“Conversely, BAs and FXR ligands alter intestinal microbiota which may add to their therapeutic effects in both entities.53 56”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [56]
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Metadata
- Authors
- Friedman, E. S., Li, Y., Shen, T.-C. D., Jiang, J., Chau, L., Adorini, L., Babakhani, F., Edwards, J., Shapiro, D., Zhao, C., Carr, R. M., Bittinger, K., Li, H., & Wu, G. D.
- Affiliations
- University of Pennsylvania (US)
- Intercept Pharmaceuticals (United States) (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Wu, Gary D.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 155
- Issue
- 6
- Pages
- 1741-1752.e5
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6279623
- OpenAlex
- W2888639734
- Semantic Scholar
- 112d9c4c64a59c5fa23a506e2249278055eca2ff
- Cited by
- 149
- References
- 44
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 19 · 2023: 16 · 2022: 19 · 2021: 17 · 2020: 16 · 2019: 17
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (K08AA021424, R01AA026302)
- National Institute of General Medical Sciences (R01GM123056)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK106457, P30DK019525, P30DK050306)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- obeticholic acid, farnesoid X receptor, bile acids, gut microbiota, bile acid synthesis inhibition, Gram-positive bacteria, Firmicutes, bacterial growth inhibition, microbiome biomarkers
- MeSH terms
- Gastrointestinal Microbiome, Receptor, Farnesoid X-Activated, Adult, Animals, Bile Acids and Salts, Chenodeoxycholic Acid, Female, Humans, Intestine, Small, Male, Mice, Inbred C57BL, Receptors, Cytoplasmic and Nuclear, Mice, Healthy Volunteers
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