The impact of the gut microbiome on rheumatoid arthritis treatment

项目摘要 风湿性关节炎（RA）是一种炎症性关节炎，除非有效，否则会导致不可逆的损伤 快速提供治疗。口服甲氨蝶呤（MTX）是类风湿关节炎的一线治疗，但在50-70%的 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过， 人类遗传学或环境因素预测MTX反应，没有人检查肠道的作用 微生物组我们最近表明，RA患者的肠道微生物组预测MTX的反应性。我们 进一步表明，携带快速代谢MTX的肠道微生物群的RA患者不太可能 对MTX有反应，表明MTX的肠道微生物代谢有助于反应。相关基因 代谢和微生物代谢对MTX药理学的因果影响仍然未知。这 知识可以改变我们对影响MTX反应的可变因素的理解;它们可以提供 这是设计改变或靶向肠道微生物群的疗法的基础。我们将努力尝试， 假设MTX肠道细菌代谢干扰RA治疗。纳亚克博士和一名受训人员， 通过本行政补充，将研究以下独立和互补的目标：（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， 影响风湿性疾病的治疗。定义这些机制将促进我们对 微生物组在精准医疗中的作用。

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.