Microbial metabolites impacting the response to methotrexate in rheumatoid arthritis

微生物代谢物影响类风湿性关节炎对甲氨蝶呤的反应

• 批准号: 10578433
• 负责人: Renuka Rajendra Nayak
• 金额: $ 8.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578433
• 关键词: Adenosine; Affect; American; Anti-Inflammatory Agents; Antiinflammatory Effect; Arthritis; Autoimmune Diseases; Bacterial Model; Bacteroides thetaiotaomicron; Bacteroidetes; Blood; Development; Dose; Enzymes; Feces; Folic Acid; Foundations; Future; Genetic Models; Gnotobiotic; Goals; Grant; Growth; Human; Immunity; In Vitro; Individual; Inflammation; Inflammatory Arthritis; Knowledge; Link; Measures; Mediating; Metabolic; Metabolism; Methotrexate; Microbe; Molecular; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Pre-Clinical Model; Rheumatism; Rheumatoid Arthritis; Rheumatology; Role; Shapes; T-Lymphocyte; Testing; Transplantation; Work; clinical practice; cohort; cost effective; design; extracellular; gut bacteria; gut microbiome; gut microbiota; immune activation; improved; in vivo; innovation; metabolome; metabolomics; microbial; microbiota; mutant; patient response; precision medicine; responders and non-responders; response; skin disorder; targeted treatment; treatment response

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.

项目概要/摘要 低剂量甲氨蝶呤 (MTX) 是一种经济有效的一线疗法，适用于数百万炎症患者 关节炎或皮肤病，但多达 50-70% 的患者对 MTX 没有充分反应。修改因素 限制 MTX 反应将使更多患者受益于这种协同增加的锚定药物 其他抗炎药的功效。我们最近表明，类风湿性关节炎的肠道微生物组 (RA) 患者预测 MTX 反应性，增加了肠道微生物群对 MTX 起作用的可能性 回复。出乎意料的是，我们发现MTX原本是为了抑制人类叶酸酶而设计的，却发挥了生长- 对肠道微生物群的抑制作用，将暴露于 MTX 的微生物群移植到无菌小鼠中导致 免疫激活减少。这些发现表明 MTX 发挥其抗- 炎症效应是通过肠道微生物群的调节而产生的。因此，肠道微生物组可能是一个可改变的因素 可以有针对性地让更多患者从 MTX 中受益。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的机制。这些知识将使 我们专门针对这些肠道微生物机制，这可能会改善宿主的药物反应。 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。有了这些信息，我们就可以为自身免疫性疾病患者推进精准医疗。这 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 治疗风湿病和自身免疫性疾病。该应用程序的总体目标是确定 MTX 诱导的体内肠道代谢组变化并测试微生物腺苷途径在介导中的影响 MTX 反应。在这里，我们检验了这样的假设：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。采用代谢组学、细菌组学的创新组合 遗传学和关节炎的临床前模型，我们将 (1) 评估 MTX 对肠道的代谢影响 (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。这个项目意义重大，因为 MTX 非 反应影响大多数 MTX 用户，识别微生物对无反应的影响具有重要意义。 推进该领域和临床实践的潜力。它具有创新性，因为它探讨了药物与微生物群的相互作用 以及这些如何影响患者的 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，有可能使 更多患者受益于风湿病的锚定药物。