The gut microbiome in juvenile idiopathic arthritis

One in every thousand children in the United Kingdom is diagnosed with juvenile idiopathic arthritis (JIA), a persistent, early-onset inflammatory joint disease that both parallels and differs from its adult analogs (e.g. rheumatoid arthritis, spondyloarthritis). JIA is among the many chronic systemic inflammatory diseases in which the gut microbiome has been implicated, but careful multi’omic studies of this complex condition have not previously been carried out. The Inflammatory Arthritis Microbiome Consortium (IAMC) characterized JIA gut microbial ecology, metabolism, and interactions with the hosts’ immune system through shotgun metagenomic and immunotype profiles. Samples were collected from children with juvenile enthesitis-related arthritis, oligoarticular JIA, polyarticular JIA, and psoriatic arthritis for a total of 113 JIA samples, plus 38 samples collected from age matched controls. We found that JIA subtype, current arthritis modifying drugs, and HLA-B27 status all explained a significant amount of taxonomic and functional variability within the gut ecosystem (PERMANOVA R² 2-3%, q<0.25). Current C-reactive protein levels and limited joint count, which are used to determine clinical inflammation status, also explained nominal amounts of variation. Age of the patient, as expected, explained the largest portion of the taxonomic (but not functional) variation. While the spread in age across such an important and rapidly changing gut microbiome landscape made it more difficult to interpret key ecological shifts, we were able to quantify several clades that mimic the results of adults with severe arthritis. These included a loss of key gut commensals (e.g. Faecalibacterium prausnitzii) associated with inflammatory markers (e.g. limited joint counts) and increased prevalence and abundance of proinflammatory taxa such as Esherichia coli. Additionally, sub-species phylogenetic associations were found with age, current drug, and JIA subtype. Functionally, several alterations to fatty acid metabolism were identified, along with modifications across sulfur related cycling and metabolism. Untargeted metabolomic profiles have also been generated in order to link potentially causal microbial changes to mediating small molecules. Taken together, our efforts represent the first comprehensive investigation of the gut microbial landscape’s interaction with systemic inflammation during juvenile idiopathic arthritis.