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Metagenomic analysis revealed the potential role of gut microbiome in gout.

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.

SUBMITTER: Chu Y

PROVIDER: S-EPMC8352958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Microbial communities of the mouse gut have been extensively studied; however, their functional roles and regulation are yet to be elucidated. Metagenomic and metatranscriptomic analyses may allow us a comprehensive profiling of bacterial composition and functions of the complex gut microbiota. The present study aimed to investigate the active functions of the microbial communities in the murine cecum by analyzing both metagenomic and metatranscriptomic data on specific bacterial species within the microbial communities, in addition to the whole microbiome. RESULTS:Bacterial composition of the healthy mouse gut microbiome was profiled using the following three different approaches: 16S rRNA-based profiling based on amplicon and shotgun sequencing data, and genome-based profiling based on shotgun sequencing data. Consistently, Bacteroidetes, Firmicutes, and Deferribacteres emerged as the major phyla. Based on NCBI taxonomy, Muribaculaceae, Lachnospiraceae, and Deferribacteraceae were the predominant families identified in each phylum. The genes for carbohydrate metabolism were upregulated in Muribaculaceae, while genes for cofactors and vitamin metabolism and amino acid metabolism were upregulated in Deferribacteraceae. The genes for translation were commonly enhanced in all three families. Notably, combined analysis of metagenomic and metatranscriptomic sequencing data revealed that the functions of translation and metabolism were largely upregulated in all three families in the mouse gut environment. The ratio of the genes in the metagenome and their expression in the metatranscriptome indicated higher expression of carbohydrate metabolism in Muribaculum, Duncaniella, and Mucispirillum. CONCLUSIONS:We demonstrated a fundamental methodology for linking genomic and transcriptomic datasets to examine functional activities of specific bacterial species in a complicated microbial environment. We investigated the normal flora of the mouse gut using three different approaches and identified Muribaculaceae, Lachnospiraceae, and Deferribacteraceae as the predominant families. The functional distribution of these families was reflected in the entire microbiome. By comparing the metagenomic and metatranscriptomic data, we found that the expression rates differed for different functional categories in the mouse gut environment. Application of these methods to track microbial transcription in individuals over time, or before and after administration of a specific stimulus will significantly facilitate future development of diagnostics and treatments.

Project description:Little is known regarding the pool of mobile genetic elements associated with the human gut microbiome. In this study we employed the culture independent TRACA system to isolate novel plasmids from the human gut microbiota, and a comparative metagenomic analysis to investigate the distribution and relative abundance of functions encoded by these plasmids in the human gut microbiome.Novel plasmids were acquired from the human gut microbiome, and homologous nucleotide sequences with high identity (>90%) to two plasmids (pTRACA10 and pTRACA22) were identified in the multiple human gut microbiomes analysed here. However, no homologous nucleotide sequences to these plasmids were identified in the murine gut or environmental metagenomes. Functions encoded by the plasmids pTRACA10 and pTRACA22 were found to be more prevalent in the human gut microbiome when compared to microbial communities from other environments. Among the most prevalent functions identified was a putative RelBE toxin-antitoxin (TA) addiction module, and subsequent analysis revealed that this was most closely related to putative TA modules from gut associated bacteria belonging to the Firmicutes. A broad phylogenetic distribution of RelE toxin genes was observed in gut associated bacterial species (Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria), but no RelE homologues were identified in gut associated archaeal species. We also provide indirect evidence for the horizontal transfer of these genes between bacterial species belonging to disparate phylogenetic divisions, namely Gram negative Proteobacteria and Gram positive species from the Firmicutes division.The application of a culture independent system to capture novel plasmids from the human gut mobile metagenome, coupled with subsequent comparative metagenomic analysis, highlighted the unexpected prevalence of plasmid encoded functions in the gut microbial ecosystem. In particular the increased relative abundance and broad phylogenetic distribution was identified for a putative RelBE toxin/antitoxin addiction module, a putative phosphohydrolase/phosphoesterase, and an ORF of unknown function. Our analysis also indicates that some plasmids or plasmid families are present in the gut microbiomes of geographically isolated human hosts with a broad global distribution (America, Japan and Europe), and are potentially unique to the human gut microbiome. Further investigation of the plasmid population associated with the human gut is likely to provide important insights into the development, functioning and evolution of the human gut microbiota.

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Metagenomic analysis revealed the potential role of gut microbiome in gout.

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