Elliot S Friedman1, Yun Li2, Ting-Chin David Shen1, Jack Jiang1, Lillian Chau1, Luciano Adorini3, Farah Babakhani3, Jeffrey Edwards3, David Shapiro3, Chunyu Zhao4, Rotonya M Carr1, Kyle Bittinger4, Hongzhe Li2, Gary D Wu5. 1. Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 2. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 3. Intercept Pharmaceuticals, San Diego, California. 4. Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 5. Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: gdwu@pennmedicine.upenn.edu.
Abstract
BACKGROUND & AIMS: Intestinal bacteria can modify the composition of bile acids and bile acids, which are regulated by the farnesoid X receptor, affect the survival and growth of gut bacteria. We studied the effects of obeticholic acid (OCA), a bile acid analogue and farnesoid X receptor agonist, on the intestinal microbiomes of humans and mice. METHODS: We performed a phase I study in 24 healthy volunteers given OCA (5, 10, or 25 mg/d 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 meta-genomic 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 weregavage fed 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 the 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 the diet and oral microbiota. We found that bile acids decreased 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 lower endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine, compared with 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 farnesoid X receptor activation alters the intestinal microbiota and could provide opportunities for microbiome biomarker discovery or new approaches to engineering the human microbiome. ClinicalTrials.gov, NCT01933503.
RCT Entities:
BACKGROUND & AIMS: Intestinal bacteria can modify the composition of bile acids and bile acids, which are regulated by the farnesoid X receptor, affect the survival and growth of gut bacteria. We studied the effects of obeticholic acid (OCA), a bile acid analogue and farnesoid X receptor agonist, on the intestinal microbiomes of humans and mice. METHODS: We performed a phase I study in 24 healthy volunteers given OCA (5, 10, or 25 mg/d 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 meta-genomic 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 gavage fed 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 the 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 the diet and oral microbiota. We found that bile acids decreased 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 lower endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine, compared with 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 farnesoid X receptor activation alters the intestinal microbiota and could provide opportunities for microbiome biomarker discovery or new approaches to engineering the human microbiome. ClinicalTrials.gov, NCT01933503.
Authors: Y Bouhnik; S Alain; A Attar; B Flourié; L Raskine; M J Sanson-Le Pors; J C Rambaud Journal: Am J Gastroenterol Date: 1999-05 Impact factor: 10.864
Authors: Rohit Loomba; Victor Seguritan; Weizhong Li; Tao Long; Niels Klitgord; Archana Bhatt; Parambir Singh Dulai; Cyrielle Caussy; Richele Bettencourt; Sarah K Highlander; Marcus B Jones; Claude B Sirlin; Bernd Schnabl; Lauren Brinkac; Nicholas Schork; Chi-Hua Chen; David A Brenner; William Biggs; Shibu Yooseph; J Craig Venter; Karen E Nelson Journal: Cell Metab Date: 2017-05-02 Impact factor: 27.287
Authors: Charlie G Buffie; Vanni Bucci; Richard R Stein; Peter T McKenney; Lilan Ling; Asia Gobourne; Daniel No; Hui Liu; Melissa Kinnebrew; Agnes Viale; Eric Littmann; Marcel R M van den Brink; Robert R Jenq; Ying Taur; Chris Sander; Justin R Cross; Nora C Toussaint; Joao B Xavier; Eric G Pamer Journal: Nature Date: 2014-10-22 Impact factor: 49.962
Authors: Gideon M Hirschfield; Andrew Mason; Velimir Luketic; Keith Lindor; Stuart C Gordon; Marlyn Mayo; Kris V Kowdley; Catherine Vincent; Henry C Bodhenheimer; Albert Parés; Michael Trauner; Hanns-Ulrich Marschall; Luciano Adorini; Cathi Sciacca; Tessa Beecher-Jones; Erin Castelloe; Olaf Böhm; David Shapiro Journal: Gastroenterology Date: 2014-12-11 Impact factor: 22.682
Authors: Harold J Boutte; Jacqueline Chen; Todd N Wylie; Kristine M Wylie; Yan Xie; Mackenzie Geisman; Anirudh Prabu; Vered Gazit; Phillip I Tarr; Marc S Levin; Brad W Warner; Nicholas O Davidson; Deborah C Rubin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2021-11-24 Impact factor: 4.052
Authors: André A Weber; Elvira Mennillo; Xiaojing Yang; Lori W E van der Schoor; Johan W Jonker; Shujuan Chen; Robert H Tukey Journal: Drug Metab Dispos Date: 2020-11-05 Impact factor: 3.922