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).

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

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