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.

项目摘要 /摘要 低剂量甲氨蝶呤（MTX）是一种成本效益的一线治疗，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反应将使更多患者从这种锚定药物中受益，从而协同增加 其他抗炎药的功效。我们最近表明类风湿关节炎的肠道微生物组 （RA）患者预测MTX反应性，从而提高了肠道微生物组有助于MTX的可能性 回复。出乎意料的是，我们发现最初旨在抑制人叶酸酶的MTX施加生长 - 对肠道菌群的抑制作用，并将MTX暴露的菌群移植到gnotobirotic小鼠中，导致 免疫激活降低。这些发现表明，MTX发挥其抗抗菌的一种机制 炎症作用是通过调节肠道菌群的调节。因此，肠道微生物组可能是可修改的因素 这可以作为目标是使更多患者从MTX中受益。然而，仍然缺乏知识 MTX-Microbiota相互作用塑造宿主免疫的机制。这样的知识将使 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，有至关重要的需要确定MTX影响菌群以形成宿主的机制 免疫。有了这些信息，我们可以为患有自身免疫性疾病的患者推进精确药物。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 风湿性和自身免疫性疾病的治疗。此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响应。在这里，我们测试了MTX作用于肠道菌群以增加细胞外的假设 腺苷并减少宿主的炎症。使用代谢组学，细菌的创新组合 遗传学和关节炎的临床前模型，我们将（1）评估MTX对肠道的代谢后果 体内菌群和（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。该项目很重要，因为MTX非 - 响应会影响大多数MTX用户，并确定对无响应的微生物贡献 推进领域和临床实践的潜力。它具有创新性，因为它可以探测药物 - 微生物群的相互作用 以及这些如何对患者的MTX反应贡献。结果可能会产生积极的影响 开发微生物指导疗法以改善MTX反应的基础，有可能实现 更多的患者从风湿病学中受益于锚固药物。