NOVEL METABOLITE AND MICROBIOTA PATHWAYS FOR HYPERURICEMIA AND GOUT

痛风是一种新陈代谢疾病，会导致最常见的炎症性关节炎，导致极度疼痛。 照明弹和关节损坏。由于尿酸盐是一种因果代谢物，痛风的风险受到生活方式的影响，而且随着越来越多的 在西方流行的生活方式中，痛风的疾病负担在全球范围内上升，目前影响到4%的美国成年人(&gt；9 随着急诊室就诊和住院人数的增加。通过NIH资助的研究，我们已经取得了 在确定痛风的生活方式和遗传风险因素、量化据称的因素以及 发现新的风险因素和新的保护性因素，以及痛风事件的常见遗传变异。 然而，在临床痛风的发展过程中，基本问题仍然存在；长期高尿酸血症(HU)是 必要的，但不充分的(只有20%的人会患痛风)。此外，这种独特的性别背后的生物学 痛风的差异(男性的患病率是女性的3倍)在很大程度上仍然不清楚。为此， 代谢组代表了基因组和表现组之间的一个引人注目的靶标特征来阐明疾病 机制、易感性、进展和预测，尤其是代谢-炎症条件，如 痛风。事实上，某些代谢物对于诱导训练有素的免疫和调节炎症是至关重要的。 基因表达，而其他可能抑制痛风炎症，增加尿酸沉淀物，或影响 促炎状态，HU进展的所有相关途径。在多个与痛风相关的疾病中 来自亚洲的代谢组学研究，加上我们来自英国生物库的新数据，已经涉及到支链 氨基酸的横截面。此外，性激素代谢物，虽然与痛风风险有关，但也 影响肠道微生物区系的组成，进而调节循环性激素水平。 此外，痛风患者也表现出细菌的枯竭，这种细菌可以通过尿酸溶解降低尿酸水平。 作为丁酸盐，一种短链游离脂肪酸代谢物，能够减轻痛风炎症。而当 非常有希望的是，目前尚不清楚这些组学特征是导致痛风风险还是代表 已建立的痛风(反向因果关系)或混淆，以及它们在亚洲或男性以外的普遍性尚不清楚。 基于我们之前在R01中取得的成功和在长期代谢组学研究方面的丰硕记录 卫生专业人员跟踪研究和两名护士的健康研究，这一竞争更新建议 首次对痛风事件进行前瞻性、基于人群的代谢组学研究，并进行外部验证 在不同的队列(ARIC，其中62%是非裔美国人)和因果推理分析(目标1)中，并澄清 肠道微生物区系的作用(目标2)，数十年确诊的痛风病例和丰富的生活方式暴露/生物标志物 数据。我们的目标是确定痛风风险的关键组学，类似于已建立的强因果代谢物。 (例如，冠状动脉事件的胆固醇)。已确定的因素有望实现新的预防和治疗。 痛风的选择和新的预测工具超越了尿酸，包括从HU进展到临床痛风 (一级预防)或可能的复发风险，以指导整体痛风护理(二级预防)。

Gout, a metabolic condition causing the most common inflammatory arthritis, leads to excruciatingly painful flares and joint damage. With urate a causal metabolite, gout risk is affected by lifestyle, and with increasingly prevalent “western” lifestyles, the disease burden of gout has risen globally, now affecting 4% of US adults (>9 million) with rising emergency room visits and hospitalizations. Through NIH-funded research, we have made significant advances in identifying lifestyle and genetic risk factors for gout, quantifying purported factors, and discovering novel risk factors and new protective ones, as well as common genetic variants for incident gout. Still, fundamental questions remain in the progression to clinical gout; prolonged hyperuricemia (HU) is necessary, but not sufficient (only ~20% develop gout). Furthermore, the biology behind the distinctive sex difference in gout (>3 times higher prevalence in men than women) remains largely unclear. To that end, the metabolome represents a compelling target trait between genome and phenome to elucidate disease mechanisms, predisposition, progression and prediction, especially for metabolic-inflammatory conditions like gout. Indeed, certain metabolites are crucial for induction of trained immunity and regulation of inflammatory gene expression, while others may suppress gouty inflammation, increase urate precipitation, or affect proinflammatory status, all relevant pathways for progression from HU. Amongst the multiple gout-related metabolomics studies, 6 from Asia, plus our new data from UK Biobank, have implicated branched-chain amino acids cross-sectionally. Furthermore, sex hormone metabolites, while implicated in gout risk, also affect the composition of gut microbiota, which can, in turn, modulate circulating sex hormone levels. Moreover, gout patients showed depletions of bacteria that can lower urate levels through uricolysis, as well as butyrate, a short chain free fatty acid metabolite capable of reducing gouty inflammation. While highly promising, it remains unknown if these omics profiles contribute to gout risk or represent ‘markers’ of established gout (reverse causation) or confounding, and their generalizability beyond Asia or males is unclear. Building on our prior R01 success and fruitful track record of long-term metabolomics research in the Health Professionals Follow-up Study and two Nurses’ Health Studies, this competing renewal proposes to conduct the first prospective, population-based metabolomics study of incident gout with external validation in a diverse cohort (ARIC, with 62% African Americans) and causal inference analysis (Aim 1), and clarify the roles of gut microbiota (Aim 2), with decades of confirmed gout cases and rich lifestyle exposure/biomarker data. We aim to determine pivotal omics in gout risk, analogous to established, strongly causal metabolites (e.g., cholesterol for coronary events). The identified factors hold the promise of new prevention and treatment options as well as novel predictive tools for gout beyond urate, including progression from HU to clinical gout (primary prevention) or possibly risk of recurrent flares to guide holistic gout care (secondary prevention).