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GENETICS-BASED ANALYSIS IDENTIFIES PLASMA GLYCOCHENODEOXYCHOLATE GLUCURONIDE AS A POTENTIAL PROTECTIVE FACTOR FOR PRIMARY SCLEROSING CHOLANGITIS

Wangjianfei Yu 1, JUN HE 2, Lei Qin 2

Affiliations

1 The First Affiliated Hospital of Soochow University, Suzhou, China|||The First Affiliated Hospital of Soochow University, Suzhou, China|||Soochow University, Suzhou, China

2 The First Affiliated Hospital of Soochow University, Suzhou, China|||The First Affiliated Hospital of Soochow University, Suzhou, China

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Abstract

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 dysfunction^1,2. 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 diseases^4,5. 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 analysed^4,8. 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.

Conference

UEG Week Berlin 2025

Topics

Hepatobiliary

Submission format

Abstract

Session

BILIARY (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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