The impact of the gut microbiome on rheumatoid arthritis treatment

肠道微生物组对类风湿关节炎治疗的影响

• 批准号: 10605661
• 负责人: Renuka Rajendra Nayak
• 金额: $ 9.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605661
• 关键词: Administrative Supplement; Affect; American; Autoimmune Diseases; Clinical; Environmental Risk Factor; Foundations; Genes; Goals; Human Genetics; Individual; Inflammatory Arthritis; Knowledge; Metabolism; Methotrexate; Oral; Pain; Patients; Pharmacology; Physicians; Predictive Factor; Rheumatism; Rheumatoid Arthritis; Rheumatology; Role; Scientist; Testing; bacterial metabolism; effective therapy; gut bacteria; gut microbiome; gut microbiota; in vivo; insight; microbial; microbiome; personalized care; precision medicine; predictive tools; response; therapy design

PROJECT ABSTRACT Rheumatoid arthritis (RA) is an inflammatory arthritis resulting in irreversible damage unless effective therapy is provided quickly. Oral methotrexate (MTX) is first-line therapy for RA but is inadequate in 50-70% of patients; clinicians currently employ a “trial and error” approach to treatment. While many have studied whether human genetics or environmental factors predict MTX response, none have examined the role of the gut microbiome. We recently showed that the gut microbiome of RA patients predicts MTX responsiveness. We further showed that RA patients harboring gut microbiota that quickly metabolized MTX were less likely to respond to MTX, suggesting gut microbial metabolism of MTX contributes to response. The genes responsible for metabolism and the causal impact of microbial metabolism on MTX pharmacology remains unknown. This knowledge could transform our understanding of modifiable factors that affect MTX response; they could provide a foundation for the design of therapies that modify or target the gut microbiota. Thus, we seek to test the hypothesis that gut bacterial metabolism of MTX interferes with RA treatment. Dr. Nayak and a trainee, supported by this administrative supplement, will investigate the following independent and complementary aims: (1) identify gut microbial genes responsible for MTX metabolism, (2) quantify the impact of the gut microbiome on MTX metabolism in vivo. The proposed studies will provide insight into the mechanisms by which the microbiome affects the treatment of rheumatologic disease. Defining these mechanisms will advance our knowledge of the role of the microbiome in precision medicine.

项目摘要 类风湿性关节炎(RA)是一种炎症性关节炎，除非有效，否则会造成不可逆转的损害 治疗提供得很快。口服甲氨蝶呤(MTX)是RA的一线治疗方法，但在50%-70%的患者中效果不佳 患者；临床医生目前采用“试错法”进行治疗。虽然许多人已经研究了 人类遗传或环境因素预测甲氨蝶呤的反应，没有人研究过肠道的作用 微生物组。我们最近发现，RA患者的肠道微生物群可以预测MTX的反应性。我们 进一步表明，具有快速代谢MTX的肠道微生物区系的RA患者不太可能 对甲氨蝶呤的反应，表明肠道微生物代谢甲氨蝶呤对反应有贡献。负责的基因 对于代谢和微生物代谢对MTX药理的因果影响尚不清楚。这 知识可以改变我们对影响MTX反应的可修改因素的理解；它们可以提供 为设计改变或靶向肠道微生物区系的疗法奠定了基础。因此，我们试图测试 甲氨蝶呤肠道细菌代谢干扰RA治疗的假说。纳亚克博士和一名实习生，支持 通过这一行政副刊，将调查以下独立和互补的目的：(1) 确定负责MTX代谢的肠道微生物基因，(2)量化肠道微生物群对 甲氨蝶呤在体内的代谢。拟议的研究将提供对微生物组 影响风湿病的治疗。定义这些机制将促进我们对 微生物组在精准医学中的作用。