Objective Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC.
Design We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling.
Results Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host–microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host–microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes.
Conclusions Our data reveal that IgG4-SC and PSC possess divergent host–microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.
- autoimmune disease
- hepatobiliary disease
- intestinal microbiology
Data availability statement
Data are available upon reasonable request. Additional data (beyond those included in the main text and Supplementary Information) are available from the corresponding author upon request.
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QL, BL and YL are joint first authors.
ML, XM and RT are joint senior authors.
Contributors XM, RT, MEG and ML designed the study. RT, XM, ML, J-YF and QW obtained funding. ML, QM and XX performed clinical diagnosis. QL, BL, YL, YW, BH, JL, YL, ZY, ZL, RC, YC, JZ, RW, QQ and MS collected samples. QL, BL and YL contributed to the data collection. QL and BL analysed and interpreted the data. QL, RT, BL and ML drafted the manuscript. XM and MEG revised the manuscript. All the authors approved the final version of the manuscript.
Funding This study was funded by the National Natural Science Foundation of China grants (#81830016, 81771732 and 81620108002 to XM, #81922010, 81873561 and 81570469 to RT, #81800504 to ML, #81421001 to J-YF, #81790634 to QW, #81300299 to ZY, #81500435 to XX), Shanghai Municipal Science and Technology Committee of Shanghai outstanding academic leaders plan (#20XD1422500 to RT), ‘Shuguang Program’ supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission (#18SG17 to RT), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (#20161311 to RT), ‘Chen Guang’ project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (#19CG16 to ML), Shanghai Sailing Program (#18YF1412900 to ML and #20YF1425500 to YW), Shanghai Rising-Star Program (#18QA1402700 to QW) and Innovative research team of high-level local universities in Shanghai.
Competing interests None declared.
Patient and public involvement statement Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research.
Provenance and peer review Not commissioned; externally peer reviewed.
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