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Integrated Multi-omics Elucidation of the Uric Acid Degradation Pathway in Limosilactobacillus fermentum M5e

ABSTRACT:

Hyperuricemia is a growing global health concern associated with gout, renal diseases, and cardiovascular disorders. Current pharmacotherapies are often limited by side effects, underscoring the need for alternative strategies. In this study, we isolated Limosilactobacillus fermentum M5e from human feces, which demonstrated exceptional uric acid (UA) degradation efficiency, reaching 85.81% after 4 days under high UA conditions (6.40 mmol/L). Genomic analysis revealed key genes involved in uric acid degradation, including APRT, XPT, and UapA. Transcriptomic and metabolomic analyses under uric acid stress showed significant changes in gene expression and metabolite levels, particularly in pathways related to purine metabolism, nitrogen assimilation, and energy production. The findings suggest that M5e can effectively utilize uric acid as a nitrogen source while mitigating oxidative stress. This integrated multi-omics analysis not only provides a comprehensive understanding of M5e's metabolic response to uric acid but also highlights its potential as a probiotic for managing hyperuricemia and related disorders. These insights establish L. fermentum M5e as a promising probiotic candidate for the management of hyperuricemia and provide a foundational framework for the development of microbiome-based therapeutics.

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

PROVIDER: MTBLS13223 | MetaboLights | 2026-01-26

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13223_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13223_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13223_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13223_LC-MS_positive_hilic_metabolite_profiling_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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Integrated Multi-omics Elucidation of the Uric Acid Degradation Pathway in Limosilactobacillus fermentum M5e

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