Liu Qiaoyan, Huang Bingyuan, Zhou Yijun, Wei Yiran, Li Yikang, Li Bo, Li You, Zhang Jun, Qian Qiwei, Chen Ruiling, Lyu Zhuwan, Wang Rui, Cao Qin, Xu Qun, Wang Qixia, Miao Qi, You Zhengrui, Lian Min, Gershwin Merrill Eric, Jin Qiaofei, Xiao Xiao, Ma Xiong, Tang Ruqi
Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Hepatology, Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.
Med. 2025 Jan 10;6(1):100504. doi: 10.1016/j.medj.2024.08.003. Epub 2024 Sep 20.
Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC.
We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts.
PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridia microbiomes, Clostridia microbiomes were more similar to healthy controls. Notably, patients in the Clostridia subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridia subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridia subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridia group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts.
Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies.
This research was mainly supported by the National Natural Science Foundation of China.
原发性胆汁性胆管炎（PBC）是一种进行性自身免疫性肝病。对熊去氧胆酸（UDCA）反应不足会导致发展为终末期肝病的高风险。肠道微生物群失调与PBC有关。在此，我们旨在研究能够进行风险分层的微生物特征，并为PBC的新疗法提供机制性见解。
我们前瞻性招募了未接受过UDCA治疗的PBC患者，并使用治疗前（n = 132）和治疗后（n = 59）获得的粪便和血清样本进行宏基因组测序和代谢组学分析。使用无监督机器学习方法鉴定PBC微生物组亚型，并在两个独立队列中进行验证。
PBC基线宏基因组聚为两种群落亚型，其特征为梭菌属分类群丰度不同。与非梭菌微生物组相比，梭菌微生物组与健康对照更相似。值得注意的是，梭菌亚型患者的UDCA无反应率比非梭菌亚型患者高2倍（41%对20%，p = 0.015）。宏基因组和代谢组数据的综合分析揭示了两个元群落之间不同的功能模块和代谢活动。特别是，对免疫调节和肠道屏障维持至关重要的厌氧发酵以及生物活性代谢物（包括色氨酸衍生物和次级胆汁酸）的产生在梭菌亚型中明显减少。此外，UDCA给药仅在非梭菌组中重新配置了粪便微生物和代谢谱。重要的是，微生物组亚型及其与UDCA反应的关联在两个独立的未接受过治疗的PBC队列中具有可重复性。
表征基线微生物群模式可能有助于预测PBC的治疗结果，并促进个性化治疗策略。
本研究主要由中国国家自然科学基金资助。
