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Original Article
Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD
  1. Na Jiao1,
  2. Susan S Baker2,3,
  3. Adrian Chapa-Rodriguez2,
  4. Wensheng Liu2,
  5. Colleen A Nugent2,
  6. Maria Tsompana4,
  7. Lucy Mastrandrea5,
  8. Michael J Buck3,4,
  9. Robert D Baker2,
  10. Robert J Genco3,6,
  11. Ruixin Zhu1,
  12. Lixin Zhu2,3
  1. 1Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China
  2. 2Department of Pediatrics, Digestive Diseases and Nutrition Center, The State University of New York at Buffalo, Buffalo, New York, USA
  3. 3Genome, Environment and Microbiome Community of Excellence, The State University of New York at Buffalo, Buffalo, New York, USA
  4. 4Department of Biochemistry and Center of Excellence in Bioinformatics and Life Sciences, The State University of New York at Buffalo, Buffalo, New York, USA
  5. 5Division of Endocrinology, Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA
  6. 6Departments of Oral Biology, Microbiology and Immunology, The State University of New York at Buffalo, Buffalo, New York, USA
  1. Correspondence to Dr Susan S Baker, Department of Pediatrics, SUNY at Buffalo, 3435 Main Street, 422 BRB, Buffalo 14214, New York, USA; sbaker{at}upa.chob.edu, Professor Ruixin Zhu, Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China; rxzhu{at}tongji.edu.cn and Dr Lixin Zhu, Department of Pediatrics, SUNY at Buffalo, 3435 Main Street, 422 BRB, Buffalo 14214, New York, USA; lixinzhu{at}buffalo.edu

Abstract

Objective Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.

Design Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.

Results Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.

Conclusions The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

  • bile acid
  • bile acid metabolism
  • nonalcoholic steatohepatitis
  • intestinal microbiology
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Footnotes

  • Contributors LZ, SSB and RZ conceived and designed the study. NJ, SSB, AC-R, WL, CAN and MT performed the experiments. LZ, SSB, RZ, NJ, AC-R, WL, MJB, RDB, RJG and LM analysed the data. LZ, SSB, RZ, NJ and AC-R wrote the draft of manuscript. WL, CAN, MT, LM, MJB, RDB and RJG critically revised the manuscript.

  • Funding This work was supported by National Natural Science Foundation of China (No 31200986 and No 41530105, to RZ), Natural Science Foundation of Shanghai (No 16ZR1449800, to RZ), the University at Buffalo Departmental StartUp Fund (to LZ), GEM Community of Excellence, the University at Buffalo (to LZ) and the Peter and Tommy Fund, Buffalo, NY (to SSB and LZ).

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval Children and Youth Institutional Review Board of The State University of New York at Buffalo.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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