Advertisement

Comprehensive Analysis of Serum and Fecal Bile Acid Profiles and Interaction with Gut Microbiota in Primary Biliary Cholangitis

  • Weihua Chen
  • Yiran Wei
  • Aizhen Xiong
  • Yanmei Li
  • Huida Guan
  • Qixia Wang
  • Qi Miao
  • Zhaolian Bian
  • Xiao Xiao
  • Min Lian
  • Jun Zhang
  • Bo Li
  • Qin Cao
  • Zhuping Fan
  • Weici Zhang
  • Dekai Qiu
  • Jingyuan Fang
  • M. Eric Gershwin
  • Li YangEmail author
  • Ruqi TangEmail author
  • Xiong MaEmail author
Article

Abstract

Accumulation of bile acids (BAs) contributes significantly to the pathogenesis of primary biliary cholangitis (PBC). Here, we sought to systematically characterize the serum and fecal BA profiles and the linkage between BAs and gut microbiota in PBC. The serum and fecal BAs were compared between 65 UDCA treatment-naive PBC and 109 healthy controls using UPLC-MS in cross-sectional study. In a prospective study, a subgroup of patients was enrolled for BA and microbiota analysis before and after UDCA therapy. BA compositions in serum and feces significantly differed between treatment-naive PBC and controls. Particularly, PBC was associated with decreased conversions of conjugated to unconjugated, and primary to secondary BAs, indicating impaired microbial metabolism of BAs. PBC patients at advanced stage exhibited a more abnormal BA profile compared with early-stage patients. UDCA treatment led to a decreased level of taurine-conjugated BAs, thereby reversing the conjugated/unconjugated ratio in PBC. Moreover, the level of secondary BAs such as DCA and conjugated DCA inversely correlated with PBC-enriched gut microbes (e.g., Veillonella, Klebsiella), while positively correlated with control-enriched microbes (e.g., Faecalibacterium, Oscillospira). Microbiota analysis also revealed a significant increase of taurine-metabolizing bacteria Bilophila spp. in patients after UDCA, which was strongly correlated with decreased taurine-conjugated BAs. In addition, serum FGF19 was remarkably increased in treatment-naïve PBC and decreased after UDCA. Our study established specific alterations of BA compositions in serum and feces of PBC, suggesting the potential for using BAs for diagnosis, and highlighting the possibility of modulating BA profile by altering gut microbiota.

Graphical Abstract

Keywords

Primary biliary cholangitis Bile acids Gut microbiota Ursodeoxycholic acid 

Abbreviations

PBC

Primary biliary cholangitis

UDCA

Ursodeoxycholic acid

BA

Bile acid

CA

Cholic acid

TCA

Taurocholic acid

GCA

Glycocholic acid

DCA

Deoxycholic acid

TDCA

Taurodeoxycholic acid

GDCA

Glycodeoxycholic acid

CDCA

Chenodeoxycholic acid

TCDCA

Taurochenodeoxycholic acid

GCDCA

Glycochenodeoxycholic acid

TUDCA

Tauroursodeoxycholic acid

GUDCA

Glycoursodeoxycholic acid

HDCA

Hyodeoxycholic acid

THDCA

Taurohyodeoxycholic acid

LCA

Lithocholic acid

TLCA

Taurolithocholic acid

UPLC-MS

Ultra-performance liquid chromatography/mass spectrometry

BSH

Bile salt hydrolase

CYP7A1

Cholesterol 7α-hydroxylase

FXR

Farnesoid X receptor

FGF19

Fibroblast growth factor 19

AKP

Alkline phosphatase

GGT

γ-Glutamyl transferase

ALT

Alanine aminotransferase

AST

Aspartate transaminase

IgM

Immunoglobulin M

ULN

Upper limit of normal

BMI

Body mass index

GEE

Generalized estimated equation

FDR

False discovery rate

Notes

Acknowledgements

We are grateful for all the subjects who participated in the study.

Financial Support

This work was supported by the National Natural Science Foundation of China grants (#81620108002, 81771732, and 81830016 to XM, # 81570469 and 81873561 to RT, #81573581 to LY, #81421001 to JF, #81500435 to XX) and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (#20161311 to RT).

Author Contributions

XM, RT, LY, and MEG designed and supervised the project; XM, RT, LY, and JF obtained funding. QW, ML, QM, and DQ performed clinical diagnosis and treatment. WC, YW, YL, BL, ZB, QC, and PF collected samples. YW, YL, AX, HG, and JZ contributed to data collection. YW, YL, and WC performed the experiments. RT, YW, YL, and AX performed bioinformatics and statistical analysis; interpreted data. RT, YW, and WC drafted the manuscript. WZ, XM, MEG, and LY revised the manuscript for important content.

Compliance with Ethical Standards

Competing Interests

None declared.

Supplementary material

12016_2019_8731_MOESM1_ESM.pdf (7.5 mb)
ESM 1 (PDF 7660 kb)

References

  1. 1.
    Carey EJ, Ali AH, Lindor KD (2015) Primary biliary cirrhosis. Lancet. 386:1565–1575CrossRefPubMedGoogle Scholar
  2. 2.
    Gerussi A, Cristoferi L, Carbone M et al (2018) The immunobiology of female predominance in primary biliary cholangitis. J Autoimmun 95:124–132CrossRefPubMedGoogle Scholar
  3. 3.
    Rojas M, Restrepo-Jimenez P, Monsalve DM et al (2018) Molecular mimicry and autoimmunity. J Autoimmun 95:100–123CrossRefPubMedGoogle Scholar
  4. 4.
    Jansen PL, Ghallab A, Vartak N et al (2017) The ascending pathophysiology of cholestatic liver disease. Hepatology. 65:722–738CrossRefPubMedGoogle Scholar
  5. 5.
    Fickert P, Wagner M (2017) Biliary bile acids in hepatobiliary injury—what is the link? J Hepatol 67:619–631CrossRefPubMedGoogle Scholar
  6. 6.
    Li M, Cai SY, Boyer JL (2017) Mechanisms of bile acid mediated inflammation in the liver. Mol Asp Med 56:45–53CrossRefGoogle Scholar
  7. 7.
    Corpechot C (2012) Primary biliary cirrhosis and bile acids. Clin Res Hepatol Gastroenterol 36(Suppl 1):S13–S20CrossRefPubMedGoogle Scholar
  8. 8.
    Hohenester S, Wenniger LM, Paulusma CC et al (2012) A biliary HCO3 umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 55:173–183CrossRefPubMedGoogle Scholar
  9. 9.
    Wang Y, Aoki H, Yang J et al (2017) The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology. 65:2005–2018CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Russell DW (2003) The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 72:137–174CrossRefGoogle Scholar
  11. 11.
    Lu TT, Makishima M, Repa JJ et al (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515CrossRefGoogle Scholar
  12. 12.
    Inagaki T, Choi M, Moschetta A et al (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2:217–225CrossRefPubMedGoogle Scholar
  13. 13.
    Holt JA, Luo G, Billin AN et al (2003) Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17:1581–1591CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chascsa D, Carey EJ, Lindor KD (2017) Old and new treatments for primary biliary cholangitis. Liver Int 37:490–499CrossRefPubMedGoogle Scholar
  15. 15.
    Nevens F, Andreone P, Mazzella G et al (2016) A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375:631–643CrossRefPubMedGoogle Scholar
  16. 16.
    Kowdley KV, Luketic V, Chapman R et al (2018) A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 67:1890–1902CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Li Y, Tang R, Leung PSC et al (2017) Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun Rev 16:885–896CrossRefPubMedGoogle Scholar
  18. 18.
    Molinaro A, Wahlstrom A, Marschall HU (2018) Role of bile acids in metabolic control. Trends Endocrinol Metab 29:31–41CrossRefGoogle Scholar
  19. 19.
    Wahlstrom A, Sayin SI, Marschall HU et al (2016) Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24:41–50CrossRefPubMedGoogle Scholar
  20. 20.
    Trauner M, Fuchs CD, Halilbasic E et al (2017) New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology. 65:1393–1404CrossRefPubMedGoogle Scholar
  21. 21.
    Ma HD, Zhao ZB, Ma WT et al (2018) Gut microbiota translocation promotes autoimmune cholangitis. J Autoimmun 95:47–57CrossRefPubMedGoogle Scholar
  22. 22.
    Dilger K, Hohenester S, Winkler-Budenhofer U et al (2012) Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. J Hepatol 57:133–140CrossRefPubMedGoogle Scholar
  23. 23.
    Trottier J, Bialek A, Caron P et al (2012) Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Dig Liver Dis 44:303–310CrossRefPubMedGoogle Scholar
  24. 24.
    Bell LN, Wulff J, Comerford M et al (2015) Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis. Liver Int 35:263–274CrossRefPubMedGoogle Scholar
  25. 25.
    Tang YM, Wang JP, Bao WM et al (2015) Urine and serum metabolomic profiling reveals that bile acids and carnitine may be potential biomarkers of primary biliary cirrhosis. Int J Mol Med 36:377–385CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lv LX, Fang DQ, Shi D et al (2016) Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ Microbiol 18:2272–2286CrossRefPubMedGoogle Scholar
  27. 27.
    Li Z, Lin B, Lin G et al (2017) Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis. PLoS One 12:e0178580CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Tang R, Wei Y, Li Y et al (2018) Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 67:534–541CrossRefPubMedGoogle Scholar
  29. 29.
    Lindor KD, Gershwin ME, Poupon R et al (2009) Primary biliary cirrhosis. Hepatology. 50:291–308CrossRefPubMedGoogle Scholar
  30. 30.
    Chazouilleres O, Wendum D, Serfaty L et al (1998) Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology. 28:296–301CrossRefPubMedGoogle Scholar
  31. 31.
    Corpechot C, Chazouilleres O, Poupon R (2011) Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 55:1361–1367CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang LN, Shi TY, Shi XH et al (2013) Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study. Hepatology. 58:264–272CrossRefPubMedGoogle Scholar
  33. 33.
    Yang L, Xiong A, He Y et al (2008) Bile acids metabonomic study on the CCl4- and alpha-naphthylisothiocyanate-induced animal models: quantitative analysis of 22 bile acids by ultraperformance liquid chromatography-mass spectrometry. Chem Res Toxicol 21:2280–2288CrossRefPubMedGoogle Scholar
  34. 34.
    Kuczynski J, Stombaugh J, Walters WA, et al. (2012) Using QIIME to analyze 16S rRNA gene sequences from microbial communities. Curr Protoc Microbiol. Chapter 1:Unit 1E.5.  https://doi.org/10.1002/9780471729259.mc01e05s27
  35. 35.
    Puri P, Daita K, Joyce A, et al. (2017) The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology.  https://doi.org/10.1002/hep.29359
  36. 36.
    McCoy KD, Ronchi F, Geuking MB (2017) Host-microbiota interactions and adaptive immunity. Immunol Rev 279:63–69CrossRefPubMedGoogle Scholar
  37. 37.
    Macpherson AJ, Koller Y, McCoy KD (2015) The bilateral responsiveness between intestinal microbes and IgA. Trends Immunol 36:460–470CrossRefPubMedGoogle Scholar
  38. 38.
    ter Borg PC, Schalm SW, Hansen BE et al (2006) Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 101:2044–2050CrossRefPubMedGoogle Scholar
  39. 39.
    Laue H, Denger K, Cook AM (1997) Taurine reduction in anaerobic respiration of Bilophila wadsworthia RZATAU. Appl Environ Microbiol 63:2016–2021PubMedPubMedCentralGoogle Scholar
  40. 40.
    Joyce SA, Gahan CG (2016) Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health. Annu Rev Food Sci Technol 7:313–333CrossRefPubMedGoogle Scholar
  41. 41.
    Jones BV, Begley M, Hill C et al (2008) Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proc Natl Acad Sci U S A 105:13580–13585CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Inagaki T, Moschetta A, Lee YK et al (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 103:3920–3925CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ridlon JM, Kang DJ, Hylemon PB (2006) Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47:241–259CrossRefGoogle Scholar
  44. 44.
    Kakiyama G, Pandak WM, Gillevet PM et al (2013) Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol 58:949–955CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Tabibian JH, O'Hara SP, Trussoni CE et al (2016) Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology. 63:185–196CrossRefPubMedGoogle Scholar
  46. 46.
    Devkota S, Wang Y, Musch MW et al (2012) Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 487:104–108CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wewalka M, Patti ME, Barbato C et al (2014) Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin. J Clin Endocrinol Metab 99:1442–1451CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Schaap FG, van der Gaag NA, Gouma DJ et al (2009) High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 49:1228–1235CrossRefPubMedGoogle Scholar
  49. 49.
    Wunsch E, Milkiewicz M, Wasik U et al (2015) Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease. Sci Rep 5:13462CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mueller M, Thorell A, Claudel T et al (2015) Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol 62:1398–1404CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Weihua Chen
    • 1
  • Yiran Wei
    • 1
  • Aizhen Xiong
    • 2
  • Yanmei Li
    • 1
  • Huida Guan
    • 2
  • Qixia Wang
    • 1
  • Qi Miao
    • 1
  • Zhaolian Bian
    • 3
  • Xiao Xiao
    • 1
  • Min Lian
    • 1
  • Jun Zhang
    • 1
  • Bo Li
    • 1
  • Qin Cao
    • 4
  • Zhuping Fan
    • 4
  • Weici Zhang
    • 5
  • Dekai Qiu
    • 1
  • Jingyuan Fang
    • 1
  • M. Eric Gershwin
    • 5
  • Li Yang
    • 2
    Email author
  • Ruqi Tang
    • 1
    Email author
  • Xiong Ma
    • 1
    Email author
  1. 1.Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai Institute of Digestive DiseaseShanghaiChina
  2. 2.The MOE Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghaiChina
  3. 3.Nantong Institute of Liver Disease, Department of Gastroenterology and Hepatology, Nantong Third People’s HospitalNantong UniversityNantongChina
  4. 4.Department of Health Manage Center, School of Medicine, RenJi HospitalShanghai Jiao Tong UniversityShanghaiChina
  5. 5.Division of Rheumatology, Department of Medicine, Allergy and Clinical ImmunologyUniversity of California at DavisDavisUSA

Personalised recommendations