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

基本信息

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
项目类别：
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

项目摘要

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，除非有效治疗，否则会导致不可逆转的损害口服甲氨蝶呤 (MTX) 是治疗 RA 的一线疗法，但对于 50-70% 的患者来说效果不佳。患者；目前采用“试错”方法进行治疗，而许多人已经研究过是否可以。人类遗传学或环境因素可预测 MTX 反应，但没有研究过肠道的作用我们最近发现 RA 患者的肠道微生物组可以预测 MTX 反应性。进一步表明，具有快速代谢 MTX 的肠道微生物群的 RA 患者不太可能对 MTX 做出反应，表明 MTX 的肠道微生物代谢有助于响应的基因。代谢以及微生物代谢对 MTX 药理学的因果影响仍不清楚。知识可以改变我们对影响 MTX 反应的可改变因素的理解；为设计改变或针对肠道微生物群的疗法奠定了基础。因此，我们寻求测试。 Nayak 博士和一名实习生支持 MTX 肠道细菌代谢干扰 RA 治疗的假设。通过本行政补充，将调查以下独立和补充的目标：(1) 确定负责 MTX 代谢的肠道微生物基因，(2) 量化肠道微生物组对 MTX 代谢的影响 MTX 体内代谢。拟议的研究将深入了解微生物组的机制。影响风湿病治疗的这些机制将增进我们对风湿病的认识。微生物组在精准医学中的作用。