NOVEL METABOLITE AND MICROBIOTA PATHWAYS FOR HYPERURICEMIA AND GOUT

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).