Abstract
Emerging evidence indicates an association between gut microbiome and arthritis diseases including gout. However, how and which gut bacteria affect host urate degradation and inflammation in gout remains unclear. Here we performed a metagenome analysis on 307 fecal samples from 102 gout patients and 86 healthy controls. Gout metagenomes significantly differed from those of healthy controls. The relative abundances of Prevotella, Fusobacterium, and Bacteroides were increased in gout, whereas those of Enterobacteriaceae and butyrate-producing species were decreased. Functionally, gout patients had greater abundances for genes in fructose, mannose metabolism and lipid A biosynthesis, and lower for genes in urate degradation and short chain fatty acid production. A three-pronged association between metagenomic species, functions and clinical parameters revealed that decreased abundances of species in Enterobacteriaceae were associated with reduced amino acid metabolism and environmental sensing, which together contribute to increased serum uric acid and C-reactive protein levels in gout. A random forest classifier based on three gut microbial genes showed high predictivity for gout in both discovery and validation cohorts (0.91 and 0.80 accuracy), with high specificity in the context of other chronic disorders. Longitudinal analysis showed that uric-acid-lowering and anti-inflammatory drugs partially restored gut microbiota after 24-week treatment. Comparative analysis with obesity, type 2 diabetes, ankylosing spondylitis and rheumatoid arthritis indicated that gout metagenomes were more similar to those of autoimmune than metabolic diseases. Our results suggest that gut dysbiosis was associated with dysregulated host urate degradation and systemic inflammation and may be used as non-invasive diagnostic markers for gout.
Highlights
Gout is an inflammatory arthritis disease that primarily involves the joints and is considered a risk factor for hypertension and cardiovascular disease[1]
C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum uric acid (SUA), and other goutassociated indices including visual analog scale (VAS), arthralgia, joint swelling scores and joint tenderness scores declined in gout patients following treatment (Supplementary Data 1)
Firmicutes and Bacteroidetes exhibited moderate correlations with gout-enriched functional pathways such as carbohydrate metabolism, energy metabolism and lipid A biosynthesis. These results suggested that the decreased abundances of Enterobacteriaceae species likely contributed to reduced functional potentials in amino acid metabolism and environmental sensing, which together resulted in increased uric acid and systemic inflammation in gout patients
Summary
Gout is an inflammatory arthritis disease that primarily involves the joints and is considered a risk factor for hypertension and cardiovascular disease[1]. Gout is more common in males than females[2], with a rise in prevalence due to changes in diet and lifestyle[3]. The reported prevalence of gout in the US was 3.9% in 2015–20164, while in European countries it was ranged between 1 and 4% from 2003 to 20145. A meta-analysis of 30 studies revealed the prevalence of gout in mainland China was ~1.1% from 2000 to. Despite a relatively lower prevalence of gout in China, it shows an ascending trend by year[6]. Gout is known to be primarily caused by an abnormal increase in uric acid and the crystallization of monosodium urate (MSU)
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