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
{"title":"肠道微生物组模式影响原发性胆汁性胆管炎的治疗反应。","authors":"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","doi":"10.1016/j.medj.2024.08.003","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridia<sup>low</sup> microbiomes, Clostridia<sup>high</sup> microbiomes were more similar to healthy controls. Notably, patients in the Clostridia<sup>low</sup> subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridia<sup>high</sup> 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<sup>low</sup> subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridia<sup>high</sup> group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts.</p><p><strong>Conclusions: </strong>Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies.</p><p><strong>Funding: </strong>This research was mainly supported by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8000,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Gut microbiome pattern impacts treatment response in primary biliary cholangitis.\",\"authors\":\"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\",\"doi\":\"10.1016/j.medj.2024.08.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridia<sup>low</sup> microbiomes, Clostridia<sup>high</sup> microbiomes were more similar to healthy controls. Notably, patients in the Clostridia<sup>low</sup> subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridia<sup>high</sup> 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<sup>low</sup> subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridia<sup>high</sup> group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts.</p><p><strong>Conclusions: </strong>Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies.</p><p><strong>Funding: </strong>This research was mainly supported by the National Natural Science Foundation of China.</p>\",\"PeriodicalId\":29964,\"journal\":{\"name\":\"Med\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-09-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Med\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.medj.2024.08.003\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2024.08.003","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Gut microbiome pattern impacts treatment response in primary biliary cholangitis.
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 Clostridialow microbiomes, Clostridiahigh microbiomes were more similar to healthy controls. Notably, patients in the Clostridialow subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridiahigh 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 Clostridialow subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridiahigh 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.
期刊介绍：
Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically.
Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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