Microbial metabolites impacting the response to methotrexate in rheumatoid arthritis

项目总结/摘要 低剂量甲氨蝶呤（MTX）是一种具有成本效益的一线治疗数百万人的炎性 然而，MTX对关节炎或皮肤病的疗效不佳，但多达50 - 70%的患者对MTX没有充分的反应。修改因素 限制MTX反应将使更多的患者受益于这种协同增加的锚药物 其他抗炎药的疗效。我们最近发现类风湿性关节炎的肠道微生物组 (RA)患者预测MTX反应性，提高肠道微生物组有助于MTX的可能性 反应出乎意料的是，我们发现最初旨在抑制人类叶酸酶的MTX会发挥生长作用- 对肠道微生物群的抑制作用，以及将MTX暴露的微生物群移植到gnotobiotic小鼠中， 降低免疫激活。这些发现表明，MTX发挥其抗肿瘤作用的一种机制， 炎症作用是通过调节肠道微生物群。因此，肠道微生物组可能是一个可改变的因素 可以有针对性地使更多的患者受益于MTX。然而，仍然缺乏的是知识， MTX-微生物群相互作用塑造宿主免疫力的机制。这些知识将使 我们可以专门针对这些肠道微生物机制，这可能会导致宿主中药物反应的改善。 因此，迫切需要确定MTX影响微生物群以塑造宿主的机制。 免疫力有了这些信息，我们可以为自身免疫性疾病患者推进精准医疗。的 我们实验室的长期目标是确定人类肠道微生物组影响的分子机制 风湿性和自身免疫性疾病的治疗。本申请的总体目标是确定 MTX诱导的体内肠道代谢组学变化，并测试微生物腺苷途径介导的 MTX反应。在这里，我们测试的假设，MTX作用于肠道微生物群，以增加细胞外 腺苷并减少宿主的炎症。利用代谢组学、细菌学和 遗传学和关节炎的临床前模型，我们将（1）评估MTX对肠道代谢的影响， （2）测试微生物腺苷代谢对体内MTX反应的影响。我们 期望确定影响MTX反应的微生物机制。这个项目是重要的，因为MTX非- 反应影响了大多数MTX使用者，确定微生物对无反应的贡献， 推进该领域和临床实践的潜力。它是创新的，因为它探测药物-微生物群相互作用 以及这些因素如何影响患者的MTX反应。结果可能会产生积极的影响， 为开发微生物导向疗法以改善MTX反应奠定了基础， 更多的患者受益于风湿病学中的锚药。

PROJECT SUMMARY / ABSTRACT Low-dose methotrexate (MTX) is a cost-effective, first-line therapy for millions of individuals with inflammatory arthritis or skin disease, but as many as 50-70% of patients do not adequately respond to MTX. Modifying factors that limit MTX response would enable more patients to benefit from this anchor drug that synergistically increases the efficacy of other anti-inflammatory drugs. We recently showed that the gut microbiome of rheumatoid arthritis (RA) patients predicts MTX responsiveness, raising the possibility that the gut microbiome contributes to MTX response. Unexpectedly, we found that MTX, originally designed to inhibit human folate enzymes, exerts growth- inhibitory effects on gut microbiota, and transplantation of MTX-exposed microbiotas into gnotobiotic mice led to decreased immune activation. These findings suggest that one mechanism by which MTX exerts its anti- inflammatory effects is via modulation of the gut microbiota. Thus, the gut microbiome may be a modifiable factor that can be targeted to enable more patients to benefit from MTX. What remains lacking, however, is knowledge of the mechanisms by which MTX-microbiota interactions shape host immunity. Such knowledge would enable us to specifically target these gut microbial mechanisms, which may lead to improved drug response in the host. There is, therefore, a critical need to identify mechanisms by which MTX affects the microbiota to shape host immunity. With this information, we can advance precision medicine for patients with autoimmune disease. The long-term goal of our lab is to identify the molecular mechanisms by which the human gut microbiome impacts the treatment of rheumatic and autoimmune diseases. The overall objectives of this application are to identify MTX-induced gut metabolomic changes in vivo and test the impact of microbial adenosine pathways in mediating MTX response. Here we test the hypothesis that MTX acts on the gut microbiota to increase extracellular adenosine and reduce inflammation in the host. Using an innovative combination of metabolomics, bacterial genetics, and pre-clinical models of arthritis, we will (1) evaluate the metabolic consequences of MTX on gut microbiota in vivo, and (2) test the impact of microbial adenosine metabolism on MTX response in vivo. We expect to identify microbial mechanisms that impact MTX response. This project is significant because MTX non- response affects a majority of MTX users and identifying microbial contributions to non-response has the potential to advance the field and clinical practice. It is innovative because it probes drug-microbiota interactions and how these contribute to MTX response in patients. The results may have a positive impact by laying the foundation for the development of microbially-directed therapies to improve MTX response, potentially enabling a greater number of patients to benefit from an anchor drug in rheumatology.