Gut microbiome pattern impacts treatment response in primary biliary cholangitis.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2024-09-19 DOI:10.1016/j.medj.2024.08.003

Qiaoyan Liu, Bingyuan Huang, Yijun Zhou, Yiran Wei, Yikang Li, Bo Li, You Li, Jun Zhang, Qiwei Qian, Ruiling Chen, Zhuwan Lyu, Rui Wang, Qin Cao, Qun Xu, Qixia Wang, Qi Miao, Zhengrui You, Min Lian, Merrill Eric Gershwin, Qiaofei Jin, Xiao Xiao, Xiong Ma, Ruqi Tang

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Findings: PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridia^low microbiomes, Clostridia^high microbiomes were more similar to healthy controls. Notably, patients in the Clostridia^low subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridia^high 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^low subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridia^high group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts.

Conclusions: Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies.

Funding: This research was mainly supported by the National Natural Science Foundation of China.

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肠道微生物组模式影响原发性胆汁性胆管炎的治疗反应。

背景：原发性胆汁性胆管炎（PBC）是一种进展性自身免疫性肝病。如果对熊去氧胆酸（UDCA）的反应不充分，就很有可能发展为终末期肝病。肠道菌群失调与 PBC 有关。在此，我们旨在研究微生物特征，以便进行风险分层，并为 PBC 的新型疗法提供机理见解：我们前瞻性地招募了未经 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了元基因组测序和代谢组分析。采用无监督机器学习方法确定了 PBC 微生物组亚型，并在两个独立队列中进行了验证：研究结果：PBC 基线元基因组分为两种群落亚型，梭状芽孢杆菌类群的丰度各不相同。与Clostridialow微生物组相比，Clostridiahigh微生物组与健康对照组更为相似。值得注意的是，与 Clostridiahigh 亚型的患者相比，Clostridialow 亚型患者的 UDCA 无应答率高 2 倍（41% 对 20%，p = 0.015）。对元基因组和代谢组数据的综合分析表明，这两个元群落的功能模块和代谢活动存在差异。尤其是厌氧发酵和生物活性代谢物的产生，包括色氨酸衍生物和次级胆汁酸，对免疫调节和肠道屏障的维护至关重要，在梭状芽孢杆菌亚型中明显减少。此外，只有在 Clostridiahigh 组中，服用 UDCA 才会重新配置粪便微生物和代谢谱。重要的是，微生物群亚型及其与 UDCA 反应的关系在两个独立的治疗无效 PBC 队列中具有可重复性：结论：确定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的制定：本研究主要由国家自然科学基金资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

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