Abstract

Although gut dysbiosis had been demonstrated to be an important factor affecting hyperuricemia (HUA) and gout, little is known for its potential mechanistic connections. In this study, Uox-KO mice model that with spontaneously developed pronounced HUA and urate nephropathy was used to explore the pathophysiologic mechanism of microbiota alterations in HUA and gout with integrated multi-omics analysis. 16S rRNA gene sequencing was performed to characterize the characteristic bacteria, and untargeted LC/MS analysis was applied to reveal the featured metabolites. Our results showed there was a significant shift in gut microbiota composition and function in Uox-KO mice compared to WT mice and apparent metabolomics differences between the two groups. Among them, amino acids metabolism appears to play a critical role. Correlation analysis further revealed that the characteristic metabolites were strongly influenced by the discrepant bacterial genera. Furthermore, impairment of intestinal integrity and profound alterations in the profile of solute carrier family resulted in dysregulation of amino acids transportation, which subsequently impacted serum uric acid level and CD4+ Th17 driven inflammation. Together, these data indicate that gut dysbiosis promotes purine metabolism disorder and inflammation in Uox-KO mice. Remodeling the gut microbiota is a promising strategy to combat HUA and gout.

Highlights

  • Hyperuricemia (HUA) is a metabolic disorder caused by abnormal uric acid (UA) metabolism, and it has become the second most common metabolic disease with changes in lifestyle and dietary patterns [1]

  • We revealed that gut microbiota composition and amino acid (AA) metabolism are critical important for the catabolism of purine nucleotides and infiltration of CD4+ Th17 cells, which plays important roles in HUA and gouty inflammation

  • Cumulative evidence has demonstrated a great role for the gut microbiota and their metabolites in the pathogenesis of HUA and gout [22]

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Summary

Introduction

Hyperuricemia (HUA) is a metabolic disorder caused by abnormal uric acid (UA) metabolism, and it has become the second most common metabolic disease with changes in lifestyle and dietary patterns [1]. Uncontrolled HUA and gout can cause significant joint and organ damage [3]. HUA and associated gout have been mainly defined as the result of insufficient kidney UA excretion, emerging evidence highlights the importance of the intestinal tract and colonized gut microbiota in the development of HUA and gout [5]. Gut microbiota and its metabolites have been proven to directly or indirectly participate in the metabolism of purine and UA [7,8,9]. The intestine and gut microbiota have become a new target for the prevention and treatment of HUA and gout [11, 12]

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