# NOVEL METABOLITE AND MICROBIOTA PATHWAYS FOR HYPERURICEMIA AND GOUT

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $779,329

## Abstract

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 an...

## Key facts

- **NIH application ID:** 10444188
- **Project number:** 2R01AR065944-06A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HYON K CHOI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $779,329
- **Award type:** 2
- **Project period:** 2013-09-20 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444188

## Citation

> US National Institutes of Health, RePORTER application 10444188, NOVEL METABOLITE AND MICROBIOTA PATHWAYS FOR HYPERURICEMIA AND GOUT (2R01AR065944-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444188. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*