Association of Hyperuricemia With Immune Disorders and Intestinal Barrier Dysfunction.

Qiulan Lv,Wan Yang,Xuena Cui,Xuezhi Zhang,Peng Zhao,Xiu Liu,Xiaomin Yang,Guanpin Yang,Shichao Xing,Daxing Xu

doi:10.3389/fphys.2020.524236

Abstract

BackgroundMore than 30–40% of uric acid is excreted via the intestine, and the dysfunction of intestinal epithelium disrupts uric acid excretion. The involvement of gut microbiota in hyperuricemia has been reported in previous studies, but the changes and mechanisms of intestinal immunity in hyperuricemia are still unknown.MethodsThis study developed a urate oxidase (Uox)-knockout (Uox–/–) mouse model for hyperuricemia using CRISPR/Cas9 technology. The lipometabolism was assessed by measuring changes in biochemical indicators. Furthermore, 4-kDa fluorescein isothiocyanate–labeled dextran was used to assess gut barrier function. Also, 16S rRNA sequencing was performed to examine the changes in gut microbiota in mouse feces. RNA sequencing, Western blot, Q-PCR, ELISA, and immunohistochemical analysis were used for measuring gene transcription, the number of immune cells, and the levels of cytokines in intestinal tissues, serum, kidney, liver, pancreas, and vascellum.ResultsThis study showed that the abundance of inflammation-related microbiota increased in hyperuricemic mice. The microbial pattern recognition–associated Toll-like receptor pathway and inflammation-associated TNF and NF-kappa B signaling pathways were significantly enriched. The increased abundance of inflammation-related microbiota resulted in immune disorders and intestinal barrier dysfunction by upregulating TLR2/4/5 and promoting the release of IL-1β and TNF-α. The levels of epithelial tight junction proteins occludin and claudin-1 decreased. The expression of the pro-apoptotic gene Bax increased. The levels of LPS and TNF-α in systemic circulation increased in hyperuricemic mice. A positive correlation was observed between the increase in intestinal permeability and serum levels of uric acid.ConclusionHyperuricemia was characterized by dysregulated intestinal immunity, compromised intestinal barrier, and systemic inflammation. These findings might serve as a basis for future novel therapeutic interventions for hyperuricemia.

Highlights

Hyperuricemia is a systemic disease caused by purine metabolic disorder
Studies have shown that gut microbiota was considerably altered in patients with gout (Crane, 2013; Guo et al, 2016; Shao et al, 2017). These findings suggest that the gut could be a promising new therapeutic target for hyperuricemia
Significant differences were detected in the serum levels of uric acid between the two groups (Figure 1A)

Summary

Introduction

Hyperuricemia is a systemic disease caused by purine metabolic disorder. It is often a result of gout and renal disease, and accompanied by metabolic syndrome (Johnson et al, 2013; Debosch et al, 2014; Abeles, 2015). Lu et al (2018) showed that hyperuricemia was associated with metabolic disorders in a urate oxidase (Uox)-knockout mouse model. Both clinical and basic studies supported the hypothesis that hyperuricemia was an independent risk factor for hypertension and cardiovascular diseases. The involvement of gut microbiota in hyperuricemia has been reported in previous studies, but the changes and mechanisms of intestinal immunity in hyperuricemia are still unknown

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Results

Conclusion