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Microbiota Reprogramming Driven by 7,8-Dihydroxyflavone Potentiates Xanthine Oxidase to Mitigate Hyperuricemia

ABSTRACT: Hyperuricemia (HUA), primarily driven by xanthine oxidase (XO)-mediated uric acid production, presents substantial challenges to both human health and livestock productivity. While conventional XO inhibitors are effective in mitigating HUA, they are often linked to severe adverse effects. In this study, we developed MiXO, an advanced high-throughput microbiome-based screening framework aimed at identifying natural products that inhibit uric acid (UA) production through microbiota-mediated XO inhibition. From a library of 131 compounds, 7,8-dihydroxyflavone (7,8-DHF) was identified as a primary candidate. In HUA mouse models, treatment with 7,8-DHF normalized serum UA levels and reduced hyperuricemia-associated pathological sequelae and renal dysfunction. Metagenomic and metabolomic analyses demonstrated that 7,8-DHF enhances the abundance of L. reuteri, which promotes the accumulation of the microbial co-metabolite catechin. Molecular docking simulations, along with subsequent in vivo validation, confirmed that catechin occupies the XO catalytic pocket, effectively providing a biochemical blockade of urate biosynthesis to alleviate hyperuricemia. Collectively, our findings establish MiXO as a robust platform for microbiome-targeted drug discovery and position 7,8-DHF as a versatile therapeutic candidate for mitigating HUA.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14398 | MetaboLights | 2026-04-29

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14398_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14398_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14398_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	m_MTBLS14398_LC-MS_positive_reverse-phase_v2_maf.tsv	Tabular

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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

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Microbiota Reprogramming Driven by 7,8-Dihydroxyflavone Potentiates Xanthine Oxidase to Mitigate Hyperuricemia

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