Intestinal microbiota and biliary system diseases.

Introduction: The incidence of biliary system diseases has been continuously increasing in the past decade. Biliary system diseases bring a heavy burden to humanity and society. However, the specific etiology and pathogenesis are still unknown. The biliary system, as a bridge between the liver and intestine, plays an indispensable role in maintaining the physiological metabolism of the body. Therefore, prevention and treatment of biliary diseases are crucial. It is worth noting that the microorganisms participate in the lipid metabolism of the bile duct, especially the largest proportion of intestinal bacteria. Methods: We systematically reviewed the intestinal microbiota in patients with gallstones (GS), non-calculous biliary inflammatory, and biliary tract cancer (BTC). And searched Pubmed, Embase and Web of science for research studies published up to November 2023. Results: We found that the abundance of Faecalibacterium genus is decreased in GS, primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and BTC. Veillonella, Lactobacillus, Streptococcus and Enterococcus genus were significantly increased in PSC, PBC and BTC. Interestingly, we found that the relative abundance of Clostridium was generally reduced in GS, PBC and BTC. However, Clostridium was generally increased in PSC. Discussion: The existing research mostly focuses on exploring the mechanisms of bacteria targeting a single disease. Lacking comparison of multiple diseases and changes in bacteria during the disease process. We hope to provide biomarkers forearly diagnosis of biliary system diseases and provide new directions for the mechanism of intestinal microbiota in biliary diseases.

The casual relationship between autoimmune diseases and multiple myeloma: a Mendelian randomization study.

Observational studies showed possible associations between systemic lupus erythematosus and multiple myeloma. However, whether there is a casual relationship between different types of autoimmune diseases (type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis, and juvenile idiopathic arthritis) and multiple myeloma (MM) is not well known. We performed a two-sample Mendelian randomization (MR) study to estimate the casual relationship. Summary-level data of autoimmune diseases were gained from published genome-wide association studies while data of MM was obtained from UKBiobank. The Inverse-Variance Weighted (IVW) method was used as the primary analysis method to interpret the study results, with MR-Egger and weighted median as complementary methods of analysis. There is causal relationship between primary sclerosing cholangitis [OR = 1.00015, 95% CI 1.000048-1.000254, P = 0.004] and MM. Nevertheless, no similar causal relationship was found between the remaining seven autoimmune diseases and MM. Considering the important role of age at recruitment and body mass index (BMI) in MM, we excluded these relevant instrument variables, and similar results were obtained. The accuracy and robustness of these findings were confirmed by sensitivity tests. Overall, MR analysis suggests that genetic liability to primary sclerosing cholangitis could be causally related to the increasing risk of MM. This finding may serve as a guide for clinical attention to patients with autoimmune diseases and their early screening for MM.

STAT activation in regulatory CD4+ T cells of patients with primary sclerosing cholangitis.

INTRODUCTION: Regulatory CD4+ T cells (Tregs) are pivotal for inhibition of autoimmunity. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology where contribution of Tregs is still unclear. Activation of the JAK-STAT pathway critically modifies functions of Tregs. In PSC, we studied activation of STAT proteins and Treg functions in response to cytokines. METHODS: In 51 patients with PSC, 10 disease controls (chronic replicative hepatitis C), and 36 healthy controls we analyzed frequencies of Foxp3+CD25+CD127lowCD4+ Tregs, their expression of ectonucleotidase CD39, and cytokine-induced phosphorylation of STAT1, 3, 5, and 6 using phospho-flow cytometry. In parallel, we measured cytokines IFN-gamma, interleukin (IL)-6, IL-2, and IL-4 in serum via bead-based immunoassays. RESULTS: In patients with PSC, ex vivo frequencies of peripheral Tregs and their expression of CD39 were significantly reduced (p < .05 each). Furthermore, serum levels of IFN-gamma, IL-6, IL-2, and IL-4 were markedly higher in PSC (p < .05 each). Unlike activation of STAT1, STAT5, and STAT6, IL-6 induced increased phosphorylation of STAT3 in Tregs of PSC-patients (p = .0434). Finally, STAT3 activation in Tregs correlated with leukocyte counts. CONCLUSIONS: In PSC, we observed enhanced STAT3 responsiveness of CD4+ Tregs together with reduced CD39 expression probably reflecting inflammatory activity of the disease.

A protective effect of inflammatory bowel disease on the severity of sclerosing cholangitis.

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC. Methods: Mdr2-deficient mice or DDC-fed mice were used as experimental models for sclerosing cholangitis. Additionally, colitis was induced in mice with experimental sclerosing cholangitis, either through infection with Citrobacter rodentium or by feeding with DSS. Lastly, fibrosis levels were determined through FibroScan analysis in people with PSC and PSC-IBD. Results: Using two distinct experimental models of colitis and two models of sclerosing cholangitis, we found that colitis does not aggravate liver pathology, but rather reduces liver inflammation and liver fibrosis. Likewise, people with PSC-IBD have decreased liver fibrosis compared to those with PSC alone. Conclusions: We found evidence that intestinal inflammation attenuates liver pathology. This study serves as a basis for further research on the pathogenesis of PSC and PSC-IBD, as well as the molecular mechanism responsible for the protective effect of IBD on PSC development. This study could lead to the discovery of novel therapeutic targets for PSC.

NGS of brush cytology samples improves the detection of high-grade dysplasia and cholangiocarcinoma in patients with primary sclerosing cholangitis: A retrospective and prospective study.

BACKGROUND: Biliary dysplasia, a precursor of cholangiocarcinoma (CCA), is a common complication of primary sclerosing cholangitis. Patients with high-grade dysplasia (HGD) or early CCA who have received oncological treatment are candidates for liver transplantation. The preoperative diagnosis of CCA or HGD is challenging, and the sensitivity of biliary brush cytology (BC) is limited. METHODS: By using next-generation sequencing (NGS), we retrospectively analyzed archived tissue samples (n=62) obtained from explanted liver tissue and CCA samples to identify oncogenic mutations that occur during primary sclerosing cholangitis carcinogenesis. BC samples were prospectively collected from patients with primary sclerosing cholangitis (n=97) referred for endoscopic retrograde cholangiography to measure the diagnostic utility of NGS combined with BC compared with traditional cytology alone. RESULTS: Mutations in KRAS, GNAS, FLT3, RNF43, TP53, ATRX, and SMAD4 were detected in archived CCA or HGD samples. KRAS, GNAS, TP53, CDKN2A, FBXW7, BRAF, and ATM mutations were detected in prospectively collected brush samples from patients with histologically verified CCA or HGD. One patient with low-grade dysplasia in the explanted liver had KRAS and GNAS mutations in brush sample. No mutations were observed in brush samples or archived tissues in liver transplantation cases without biliary neoplasia. While KRAS mutations are common in biliary neoplasms, they were also observed in patients without biliary neoplasia during surveillance. CONCLUSIONS: In summary, NGS of BC samples increased the sensitivity of detecting biliary neoplasia compared with traditional cytology. Performing NGS on BC samples may help diagnose HGD or early CCA, benefiting the timing of liver transplantation.

Novel preclinical developments of the primary sclerosing cholangitis treatment landscape.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with inflammation, fibrosis, and destruction of intra- and extrahepatic bile ducts. Despite substantial recent advances in our understanding of PSC, the only proven treatment of PSC is liver transplantation. There is an urgent unmet need to find medical therapies for this disorder. AREAS COVERED: Multiple drugs are currently under evaluation as therapeutic options for this disease. This article summarizes the literature on the various novel therapeutic options that have been investigated and are currently under development for the treatment of PSC. EXPERT OPINION: In the next decade, more than one drug will likely be approved for the treatment of the disease, and we will be looking at combination therapies for the optimal management of the disease.

[Liver transplantation in viral and autoimmune liver diseases]. / Lebertransplantation bei viralen und autoimmunen Lebererkrankungen.

BACKGROUND: Despite substantial progress in the management of viral and autoimmune liver diseases, these entities remain relevant indications for liver transplantation. AIMS: To provide an overview of the current knowledge regarding the management of viral and autoimmune liver diseases before and after liver transplantation. MATERIALS AND METHODS: Selective literature search, including current guidelines and abstracts of key scientific meetings. RESULTS AND DISCUSSION: Viral and autoimmune liver disease can be effectively treated in most cases, which has resulted in an overall decline in liver transplantations for this indication group. However, hepatitis D infection and primary sclerosing cholangitis remain difficult-to-treat liver diseases in some patients and may progress to end-stage liver disease despite best possible management. Viral or autoimmune hepatitis can lead to fulminant liver failure requiring emergency liver transplantation. In patients who are transplanted due to viral or autoimmune liver disease, specific measures to prevent recurrence of these diseases after transplantation are mandatory. In view of effective treatment modalities for chronic hepatitis B and C, even liver grafts from donors infected with these viruses can be considered for liver transplantation under certain circumstances.

[Primary sclerosing cholangitis-Diagnosis and treatment 2024]. / Primär sklerosierende Cholangitis ­ Diagnose und Therapie 2024.

The etiology of primary sclerosing cholangitis (PSC) remains unclear, which explains in part the lack of a causal treatment. The differential diagnostic distinction from the even rarer immunoglobulin 4 (IgG4)-associated cholangitis (IAC) is becoming increasingly more successful. Advances in the understanding of different clinical courses, improvements in noninvasive diagnostics through modern magnetic resonance imaging (MRI) and the introduction of liver elastography have led to the development of improved prognostic models. The evidence for recommendations on medicinal (e.g., ursodeoxycholic acid) or endoscopic treatment (e.g., balloon dilatation and/or stent insertion) for PSC is still low. In contrast, the long-term results of liver transplantation in PSC patients are constantly improving. Due to the lack of highly sensitive and specific screening methods the early recognition of cholangiocellular carcinoma (CCC) as the most important complication is rarely successful. The continuous improvement of endoscopic retrograde cholangiopancreatography (ERCP) and direct cholangioscopy in combination with molecular biological and fluorescence in situ hybridization (FISH) analyses of bile duct tissue samples are promising for refined diagnostics. Due to the significantly increased risk of colorectal cancer, an annual colonoscopy is recommended in the presence of inflammatory bowel disease. Improvement of the early diagnostics of PSC and successful testing of new treatment strategies raise hope for a continuous improvement in the medical support of these complex patients.

Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): A matched analysis from the Paediatric PSC Consortium.

BACKGROUND: Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS: Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS: In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS: 113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION: Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

The prevalence and disease course of autoimmune liver diseases in Greenland.

Autoimmune liver diseases are rare serious diseases causing chronic inflammation and fibrosis in the liver parenchyma and bile ducts. Yet, the prevalence and burden of autoimmune liver diseases are largely unexplored in Arctic native populations. We investigated the prevalence and management of autoimmune liver diseases in Greenland using nationwide cross-sectional register data and subsequent medical chart reviews validating diagnoses and extracting liver histology examinations and medical treatments. The overall prevalence of autoimmune liver diseases in Greenland was 24.6 per 100,000 (95% CI: 14.7-41.3). This was based on 7 patients with autoimmune hepatitis (AIH) (12.3 per 100,000), 3 patients with primary biliary cholangitis (PBC) (5.3 per 100,000), 4 patients with AIH/PBC overlap disease (7.0 per 100,000), and no patients with primary sclerosing cholangitis. All diagnoses were confirmed by liver histology examinations. Medical treatments adhered to internal recommendations and induced complete remission in most patients with AIH, and complete or partial remission in 1 patient with PBC and 3 patients with AIH/PBC overlap disease. One patient had established cirrhosis at the time of diagnosis, while 2 patients progressed to cirrhosis. In conclusion, the prevalence of autoimmune liver diseases was lower in Greenland than in Scandinavia and among Alaska Inuit.

The role of donor sex on the post-liver transplant outcomes in patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) can result in hepatic decompensation and require liver transplantation (LT). This study investigates the effect of the sex of the donor and recipient as a prognostic risk factor for adverse outcomes after LT in patients with PSC. METHODS: UNOS registry was used to select LT patients with PSC from 1987 to 2019. The study cohort was stratified based on the sex of the recipient and further subdivided based on the sex of the donor. The primary endpoints of this study were all-cause mortality and graft failure, which were evaluated using a sequential Cox regression analysis. RESULTS: This study included 2829 patients; 906 female recipients were transplanted from 441 male donors and 465 female donors. 1923 male recipients were transplanted from 1194 male donors and 729 female donors. Within the mismatch analyses, the male-to-male recipients also had a significantly reduced hazard ratio of graft failure compared to female-to-male transplants [aHR 0.51, 95% confidence interval (CI) 0.33-0.79, P  = 0.003]. No difference in graft failure was observed in the mismatched female recipient subgroup. The mismatched male recipient group also showed a decreased hazard ratio of mortality from graft rejection and respiratory causes. No differences in specific mortality causes were identified in the mismatched female recipient group. CONCLUSION: This study demonstrated an increase in the risk of graft failure and mortality secondary to graft failure in male recipients of female donor livers. No differences in mortality or graft failure were identified in female recipients of male livers.

Primary Sclerosing Cholangitis Limited to Intrahepatic Bile Ducts Has Distinctly Better Prognosis.

BACKGROUND: There are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic). AIMS: This study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC. METHODS: Patients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement. RESULTS: Our cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age (mean 37.9 vs. 43.0 years, P = 0.045), the IIPSC group was not different from the extra/intrahepatic. The IIPSC group had longer transplant-free survival (log-rank P = 0.001) with a significantly lower risk for liver transplantation (12% vs. 34%, P < 0.001). The IIPSC group had a lower risk of death or transplantation than the extra/intrahepatic PSC group [HR: 0.34, 95% CI: 0.17-0.67, P < 0.001]. No bile duct or gallbladder cancers developed in patients with IIPSC, compared to 24 in the extra/intrahepatic group. The clinical characteristics and outcomes of IIPSC were similar to 23 individuals with small-duct PSC. CONCLUSIONS: Patients with IIPSC have a favorable prognosis similar to small-duct PSC. These data are important for counseling patients and designing therapeutic trials for PSC.

The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data.

Primary sclerosing cholangitis (PSC) is an inflammatory and fibrotic biliary disease lacking approved treatment. We studied CCL24, a chemokine shown to be overexpressed in damaged bile ducts, and its involvement in key disease-related mechanisms. Serum proteomics of PSC patients and healthy controls (HC) were analyzed using the Olink® proximity extension assay and compared based on disease presence, fibrosis severity, and CCL24 levels. Disease-related canonical pathways, upstream regulators, and toxicity functions were elevated in PSC patients compared to HC and further elevated in patients with high CCL24 levels. In vitro, a protein signature in CCL24-treated hepatic stellate cells (HSCs) differentiated patients by disease severity. In mice, CCL24 intraperitoneal injection selectively recruited neutrophils and monocytes. Treatment with CM-101, a CCL24-neutralizing antibody, in an α-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model effectively inhibited accumulation of peribiliary neutrophils and macrophages while reducing biliary hyperplasia and fibrosis. Furthermore, in PSC patients, CCL24 levels were correlated with upregulation of monocyte and neutrophil chemotaxis pathways. Collectively, these findings highlight the distinct role of CCL24 in PSC, influencing disease-related mechanisms, affecting immune cells trafficking and HSC activation. Its blockade with CM-101 reduces inflammation and fibrosis and positions CCL24 as a promising therapeutic target in PSC.

Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model.

BACKGROUND: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options. Recombinant adeno-associated virus (rAAV) provides a promising platform for gene therapy on such kinds of diseases. A microRNA (miRNA) let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated. AIM: To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a xenobiotic-induced mouse model of sclerosing cholangitis. METHODS: A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding for 2 wk or 6 wk. A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding. Upon sacrifice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation and fibrosis were evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot. RESULTS: rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk. The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers, and prevent the proliferation of cholangiocytes and biliary fibrosis. Furthermore, inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1, which consequently inhibit of NF-κB-mediated hepatic inflammation. CONCLUSION: Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis, which provides a possible clinical translation of PSC of human.

Enteroblastic cholangiocarcinoma: An uncommon, underrecognized subtype of bile duct cancer.

Enteroblastic carcinoma is clinically characterized by an elevated serum level of alpha-fetoprotein (AFP) and is histologically characterized by cancer cells with a clear cytoplasm and 'blastic' coarse chromatin. It sometimes has an element of hepatoid carcinoma; therefore, these two neoplasms are often regarded as sister entities. Although hepatoid carcinoma in the biliary tree has been reported, enteroblastic cholangiocarcinoma is extremely uncommon. In the present study, four cases of enteroblastic cholangiocarcinoma were examined. Tumors were located inside the liver (n = 2) or common bile duct (n = 2). The two intrahepatic cases had a history of primary sclerosing cholangitis, and serum AFP levels were elevated in both. One unresectable case was diagnosed by needle liver biopsy, while the remaining three underwent surgical resection. Histologically, all cases showed similar microscopic features. Cuboidal or polygonal cancer cells with the characteristic clear cytoplasm and subnuclear vacuoles were arranged in a papillary, micropapillary, tubular, or solid architecture. One case had an element of pancreatobiliary-type adenocarcinoma, while a hepatoid carcinoma element was not observed in any cases. All cases were positive for AFP, glypican 3, and SALL4, with SALL4 being the most widely expressed. Heppar-1 and arginase-1 were negative, except for one case, which was positive for Heppar-1. In conclusion, enteroblastic cholangiocarcinoma is an uncommon subtype of biliary tract malignancy. These cases may have been categorized as 'clear cell' cholangiocarcinoma. Although enteroblastic cholangiocarcinoma seems to occur more commonly in extrahepatic regions, including the gallbladder, it may also develop in the liver, particularly in patients with primary sclerosing cholangitis.

Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis.

BACKGROUND: The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression. METHODS: Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients' sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study. RESULTS: Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2-deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, ß and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC. CONCLUSIONS: The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.

Investigating the shared genetic architecture between primary sclerosing cholangitis and inflammatory bowel diseases: a Mendelian randomization study.

BACKGROUND: Several studies have found that primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are closely associated. However, the direction and causality of their interactions remain unclear. Thus, this study employs Mendelian Randomization to explore whether there are causal associations of genetically predicted PSC with IBD. METHODS: Genetic variants associated with the genome-wide association study (GWAS) of PSC were used as instrumental variables. The statistics for IBD, including ulcerative colitis (UC), and Crohn's disease (CD) were derived from GWAS. Then, five methods were used to estimate the effects of genetically predicted PSC on IBD, including MR Egger, Weighted median (WM), Inverse variance weighted (IVW), Simple mode, and Weighted mode. Last, we also evaluated the pleiotropic effects, heterogeneity, and a leave-one-out sensitivity analysis that drives causal associations to confirm the validity of the analysis. RESULTS: Genetically predicted PSC was significantly associated with an increased risk of UC, according to the study (odds ratio [OR] IVW= 1.0014, P<0.05). However, none of the MR methods found significant causal evidence of genetically predicted PSC in CD (All P>0.05). The sensitivity analysis results showed that the causal effect estimations of genetically predicted PSC on IBD were robust, and there was no horizontal pleiotropy or statistical heterogeneity. CONCLUSIONS: Our study corroborated a causal association between genetically predicted PSC and UC but did not between genetically predicted PSC and CD. Then, we identification of shared SNPs for PSC and UC, including rs3184504, rs9858213, rs725613, rs10909839, and rs4147359. More animal experiments and clinical observational studies are required to further clarify the underlying mechanisms of PSC and IBD.