Genetic Predisposition of the Gastrointestinal Microbiome and Primary Biliary Cholangitis: a Bi-directional, Two-sample Mendelian Randomization Analysis

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2023 Oct 30

PMID 37900141

Authors

Xin Luo

Xin You

Affiliations

Soon will be listed here.

Abstract

Background: The gut-liver axis indicates a close relationship between the gastrointestinal microbiome (GM) and primary biliary cholangitis (PBC). However, the causality of this relationship remains unknown. This study investigates the causal relationship between the GM and PBC using a bidirectional, two-sample Mendelian randomization (MR) analysis.

Methods: Genome-wide association data for GM and PBC were obtained from public databases. The inverse-variance weighted method was the primary method used for MR analysis. Sensitivity analyses were conducted to assess the stability of the MR results. A reverse MR analysis was performed to investigate the possibility of reverse causality.

Results: Three bacterial taxa were found to be causally related to PBC. Class Coriobacteriia (odds ratio (OR) = 2.18, 95% confidence interval (CI): 1.295-3.661, P< 0.05) and order Coriobacteriales (OR = 2.18, 95% CI: 1.295-3.661, P<0.05) were associated with a higher risk of PBC. Class Deltaproteobacteria (OR = 0.52, 95% CI: 0.362-0.742, P< 0.05) had a protective effect on PBC. There was no evidence of reverse causality between PBC and the identified bacterial taxa.

Conclusion: Previously unrecognized taxa that may be involved in the pathogenesis of PBC were identified in this study, confirming the causality between the GM and PBC. These results provide novel microbial targets for the prevention and treatment of PBC.

Citing Articles

Distinct signatures of gut microbiota and metabolites in primary biliary cholangitis with poor biochemical response after ursodeoxycholic acid treatment.

Han W, Song T, Huang Z, Liu Y, Xu B, Huang C Cell Biosci. 2024; 14(1):80.

PMID: 38879547 PMC: 11180406. DOI: 10.1186/s13578-024-01253-1.

Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota-Bile Acid-Immunity Network.

Guo Z, He K, Pang K, Yang D, Lyu C, Xu H Int J Mol Sci. 2024; 25(8).

PMID: 38673905 PMC: 11050225. DOI: 10.3390/ijms25084321.

References

Wu Y, Tan M, Jiang H, Lu X, Li X, Yang F . [Microorganisms in the urethral secretions of chronic prostatitis patients: A genomic analysis]. Zhonghua Nan Ke Xue. 2021; 27(2):114-123. View

Bowden J, Del Greco M F, Minelli C, Zhao Q, Lawlor D, Sheehan N . Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2018; 48(3):728-742. PMC: 6659376. DOI: 10.1093/ije/dyy258. View

Cordell H, Fryett J, Ueno K, Darlay R, Aiba Y, Hitomi Y . An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs. J Hepatol. 2021; 75(3):572-581. PMC: 8811537. DOI: 10.1016/j.jhep.2021.04.055. View

Lawlor D, Harbord R, Sterne J, Timpson N, Davey Smith G . Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2007; 27(8):1133-63. DOI: 10.1002/sim.3034. View

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

Li P, Wang H, Guo L, Gou X, Chen G, Lin D . Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med. 2022; 20(1):443. PMC: 9667679. DOI: 10.1186/s12916-022-02657-x. View

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

Carey E, Ali A, Lindor K . Primary biliary cirrhosis. Lancet. 2015; 386(10003):1565-75. DOI: 10.1016/S0140-6736(15)00154-3. View

Lin Y, Lin H, Wu C, Chen C, Ni Y . Pathogenic effects of Desulfovibrio in the gut on fatty liver in diet-induced obese mice and children with obesity. J Gastroenterol. 2022; 57(11):913-925. DOI: 10.1007/s00535-022-01909-0. View

10.

Kurilshikov A, Medina-Gomez C, Bacigalupe R, Radjabzadeh D, Wang J, Demirkan A . Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet. 2021; 53(2):156-165. PMC: 8515199. DOI: 10.1038/s41588-020-00763-1. View

11.

Slob E, Burgess S . A comparison of robust Mendelian randomization methods using summary data. Genet Epidemiol. 2020; 44(4):313-329. PMC: 7317850. DOI: 10.1002/gepi.22295. View

12.

Lindor K, Bowlus C, Boyer J, Levy C, Mayo M . Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 69(1):394-419. DOI: 10.1002/hep.30145. View

13.

Shim H, Chasman D, Smith J, Mora S, Ridker P, Nickerson D . A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians. PLoS One. 2015; 10(4):e0120758. PMC: 4405269. DOI: 10.1371/journal.pone.0120758. View

14.

Lindor K, Bowlus C, Boyer J, Levy C, Mayo M . Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases. Hepatology. 2021; 75(4):1012-1013. DOI: 10.1002/hep.32117. View

15.

Yan X, Bai L, Qi P, Lv J, Song X, Zhang L . Potential Effects of Regulating Intestinal Flora on Immunotherapy for Liver Cancer. Int J Mol Sci. 2023; 24(14). PMC: 10380345. DOI: 10.3390/ijms241411387. View

16.

Del Barrio M, Lavin L, Santos-Laso A, Arias-Loste M, Odriozola A, Rodriguez-Duque J . Faecal Microbiota Transplantation, Paving the Way to Treat Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2023; 24(7). PMC: 10094628. DOI: 10.3390/ijms24076123. View

17.

Bogdanos D, Baum H, Grasso A, Okamoto M, Butler P, Ma Y . Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol. 2003; 40(1):31-9. DOI: 10.1016/s0168-8278(03)00501-4. View

18.

Pabst O, Hornef M, Schaap F, Cerovic V, Clavel T, Bruns T . Gut-liver axis: barriers and functional circuits. Nat Rev Gastroenterol Hepatol. 2023; 20(7):447-461. DOI: 10.1038/s41575-023-00771-6. View

19.

Lv L, Fang D, Shi D, Chen D, Yan R, Zhu Y . Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis. Environ Microbiol. 2016; 18(7):2272-86. DOI: 10.1111/1462-2920.13401. View

20.

Waite D, Chuvochina M, Pelikan C, Parks D, Yilmaz P, Wagner M . Proposal to reclassify the proteobacterial classes and , and the phylum into four phyla reflecting major functional capabilities. Int J Syst Evol Microbiol. 2020; 70(11):5972-6016. DOI: 10.1099/ijsem.0.004213. View