Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California Davis, Davis, California, USA.
Gut. 2022 May;71(5):899-909. doi: 10.1136/gutjnl-2020-323565. Epub 2021 May 25.
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.
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.
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 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 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.
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.
IgG4 相关硬化性胆管炎（IgG4-SC）与原发性硬化性胆管炎（PSC）之间存在多种临床相似性，尽管肠道菌群失调已在 PSC 中得到广泛研究，但 IgG4-SC 中的肠道微生物群的作用尚不清楚。在此，我们旨在评估 IgG4-SC 和 PSC 中肠道微生物组和代谢组的变化。
我们对 135 名 IgG4-SC（n=34）、PSC（n=37）和健康对照者（n=64）的粪便样本进行了 16S rRNA 基因扩增子测序。一部分样本（31 例 IgG4-SC、37 例 PSC 和 45 例对照）还进行了非靶向代谢组学分析。
与对照组相比，IgG4-SC 和 PSC 中观察到 alpha 多样性降低和微生物群落移位。这些变化伴随着粪便代谢组的差异。重要的是，尽管在微生物群落组成和代谢活性方面存在一些共同的变化，但综合分析确定了 IgG4-SC 和 PSC 中存在不同的宿主-微生物关联。与 IgG4-SC 中的转氨酶相关的疾病相关菌属和代谢物往往倾向于与 IgG4-SC 相关。显著减少的 和升高的琥珀酸可能是 IgG4-SC 中肝炎症的基础。相比之下，在 PSC 中检测到微生物或代谢特征与胆汁淤积参数之间的潜在联系。特别是，包括次级胆汁酸在内的微生物衍生代谢物的一致性减少，提示涉及 PSC 胆汁淤积的新的宿主-微生物代谢途径。有趣的是，基于代谢物的预测模型在区分疾病状态方面比基于微生物的预测模型更有效。
我们的数据表明，IgG4-SC 和 PSC 具有不同的宿主-微生物相互作用，可能参与疾病的发病机制。这些数据强调了 IgG4-SC 的独特性。
