Introduction
Primary sclerosing cholangitis (PSC) is a major type of autoimmune cholestatic liver disease with unknown etiology, characterized by cholestasis, abnormal biliary epithelial homeostasis, biliary tract fibrosis and consequently liver dysfunction1,2. Notably, PSC further elevates the risk of developing cholangiocarcinoma3. Investigating the underlying causal factors could contribute to the development of novel therapeutic strategies, thereby mitigating the burden on public health systems imposed by these conditions.
Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases. The toxicity of bile acids is associated with the severity of cholestatic diseases4,5. Among all BA components, hydrophobic BAs such as chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)6 are considered the main toxic components to the bile duct epithelium and hepatocytes. Besides, glycochenodeoxycholic acid (GCDCA) has been used to model BA toxicity both in vivo and in vitro7. The clinical usefulness of plasma BA in cholestatic diseases was studied via BA profiling in cholangitis cohorts, and the clinical utility was analysed4,8. Nevertheless, no large-scale epidemiology studies have identified the causal relationship between individual components of BA and the pathogenesis of cholangitis, especially the sequence between changes in BA composition and disease onset.
In this study, we extracted summary statistics of 32 plasma BA components from the largest metabolome GWAS dataset to date9 as exposures and performed two-sample MR using 2 datasets of PSC as outcomes, followed by reverse MR, to assess the causal relationship between BAs and the pathogenesis of this disease.
Aims & Methods
We aimed to identify causal bile acid components on PSC using mendelian randomization. Summary statistics for primary sclerosing cholangitis were retrieved from European Bioinformatics Institute and FinnGen Consortium, and plasma bile acid components data were obtained from European Bioinformatics Institute. BA profiles of PSC patients by GC-MS were retrieved from published researches. Statistical analyses used the inverse variance weighted(IVW), weighted median(WM), maximum likelihood(ML) and MR-Egger algorithm, followed by various sensitivity analyses and reliability evaluation.
Results
Plasma level of glycochenodeoxycholate glucuronide(GCDCG) is negatively correlated with primary sclerosing cholangitis (IVW: OR=-0.12, p=0.0269 in EBI dataset, OR=-0.38, p=0.0299 in FinnGen dataset). No reverse causal effect was identified(IVW: p=0.7067 in EBI dataset, p=0.5158 in FinnGen dataset). GCDCG was decreased in bile of patients with PSC compared with healthy controls (logFC=-2.09, p=0.010).
| MR type | data sources | outcome
| exposure
| method
| OR
| p value
| Cochrans Q p value
| Egger intercept p value
|
|---|
| forward | EBI GWAS catalog | PSC | GCDCG level | ML | -0.1170 | 0.0135 |
|
|
| MR Egger | -0.1960 | 0.0242 | 0.4143 | 0.1469 |
| WM | -0.1813 | 0.0007 |
|
|
| IVW | -0.1158 | 0.0269 | 0.2753 |
|
| FInnGen | ML | -0.3880 | 0.0299 |
|
|
| MR Egger | -0.6690 | 0.0768 | 0.8872 | 0.3418 |
| WM | -0.5047 | 0.0294 |
|
|
| IVW | -0.3836 | 0.0299 | 0.8663 |
|
| reverse | EBI GWAS catalog
| GCDCG level
| PSC | IVW | 0.0054 | 0.7067 | 0.5615 |
|
Conclusion
Our findings provide evidence regarding the risk of primary sclerosing cholangitis for individuals with low level of plasma glycochenodeoxycholate glucuronide, and targeting the transformation of glycochenodeoxycholate into its glucuronide may be a novel therapeutic strategy to primary sclerosing cholangitis.
References
1. Dyson JK, Beuers U, Jones DEJ, et al. Primary sclerosing cholangitis. Lancet 2018;391(10139):2547-2559.
2. Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2023;21(8):2076-2087.
3. Tham EKJ, Lim RY, Koh B, et al. Prevalence of Chronic liver disease in Cholangiocarcinoma: a Meta-Analysis. Clin Gastroenterol Hepatol 2024.
4. Mousa OY, Juran BD, McCauley BM, et al. Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation. Hepatology 2021;74(1):281-295.
5. Perreault M, Białek A, Trottier J, et al. Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction. PLoS One 2013;8(11):e80994.
6. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999;159(22):2647-58.
7. Du Y, Khandekar G, Llewellyn J, et al. A Bile Duct-on-a-Chip With Organ-Level Functions. Hepatology 2020;71(4):1350-1363.
8. Tietz-Bogert PS, Kim M, Cheung A, et al. Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis. International Journal of Molecular Sciences 2018;19(10):3188.
9. Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nature Genetics 2023;55(1):44-53.
