Hidden link in gut–joint axis: gut microbes promote rheumatoid arthritis at early stage by enhancing ascorbate degradation

With great interest, we read the review article by Agus et al , which suggested that gut microbiome alterations could affect metabolic homeostasis.1 Moreover, gut microbiome alterations in concert with metabolites perturbation could contribute to the early development of rheumatoid arthritis (RA).2 We thus conducted a three-pronged association study3 on multiomics datasets to detect the potential microbiome–metabolites–arthritis link. We integrated multiomics datasets including gut metagenomics, clinical phenotypes and metabolites of blood and knee-joint synovial fluid from 122 participants in the healthy group (n=27), osteoarthritis (OA) group (n=19) and RA group (n=76), using a three-pronged association framework (figure 1, online supplemental material).3 Metagenomic genes were collapsed into metagenomic species (MGS)3 4 and grouped into KEGG functional modules (figure 1A).3 Additionally, the co-abundant metabolites were categorised into metabolite clusters using WGCNA framework (figure 1A).3 The functional modules associated with clinical phenotypes (eg, types of arthritis and levels of cytokines) were further identified and the cross-domain associations between these modules and metabolite clusters were assessed (figure 1B).3 Furthermore, the leave-one-out analysis was performed to determine the MGS that particularly contributed to the observed linkage between functional modules and clinical phenotypes (figure 1C).3### Supplementary data [gutjnl-2021-325209supp001.pdf] Figure 1 Overview of the three-pronged association framework integrating multiomics datasets. (A) Metabolites are summarised as co-abundance clusters, and microbial genes are grouped into KEGG modules and MGS, which are further filtered for statistically positive or negative associations (based on Spearman correlation) with the …