Microbiome Analytics of the Gut Microbiota in Patients With Juvenile Idiopathic Arthritis: A Longitudinal Observational Cohort Study

Abstract

Objective To assess the composition of gut microbiota in Italian and Dutch patients with juvenile idiopathic arthritis ( JIA ) at baseline, with inactive disease, and with persistent activity compared to healthy controls. Methods In a multicenter, prospective, observational cohort study, fecal samples were collected at baseline from 78 Italian and 21 Dutch treatment‐naive JIA patients with <6 months of disease duration and compared to 107 geographically matched samples from healthy children. Forty‐four follow‐up samples from patients with inactive disease and 25 follow‐up samples from patients with persistent activity were analyzed. Gut microbiota composition was determined by 16S ribosomal RNA –based metagenomics. Alpha‐ and β‐diversity were computed, and log ratios of relative abundance were compared between patients and healthy controls using random forest models and logistic regression. Results Baseline samples from Italian patients showed reduced richness compared to healthy controls ( P < 0.001). Random forest models distinguished between Italian patient baseline samples and healthy controls and suggested differences between Dutch patient samples and healthy controls (areas under the curve >0.99 and 0.71, respectively). The operational taxonomic units ( OTU s) of Erysipelotrichaceae (increased in patients) , Allobaculum (decreased in patients), and Faecalibacterium prausnitzii (increased in patients) showed different relative abundance in Italian patient baseline samples compared to controls after controlling for multiple comparisons. Some OTU s differed between Dutch patient samples and healthy controls, but no evidence remained after controlling for multiple comparisons. No differences were found in paired analysis between Italian patient baseline and inactive disease samples. Conclusion Our findings show evidence for dysbiosis in JIA patients. Only patient/control status, age, and geographic origin appear to be drivers of the microbiota profiles, regardless of disease activity stage, inflammation, and markers of autoimmunity.

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“…However, when comparing baseline samples with paired inactive disease samples, no differences in relative abundance were found. This finding may indicate that the gut microbiota profile is specific to the individuals with JIA, rather than the disease activity status …”

“…This finding may indicate that the gut microbiota profile is specific to the individuals with JIA, rather than the disease activity status. 90 Microbiota as JIA therapy response biomarkers Regarding the effect of pharmacological therapies on gut microbiota of patients with JIA, one of the first studies to describe potentially significant associations considered a group of patients with JIA-ERA treated with NSAIDs, alone or associated with sulfasalazine/methotrexate/biologics in different combinations, and a group of patients with JIA-non ERA, mainly treated with biologic drugs, such as etanercept and abatacept. Despite the low number of patients stratified by pharmacological treatment, authors observed enrichment in Collinsella (Actinobacteria), associated with exacerbation of joint disease, in patients with JIA-ERA treated with combined NSAIDs and sulfasalazine therapy.…”

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“…Finally, in the most extensive study of its kind to date, van Dijkhuizen et al obtained fecal microbiota on a total of 99 treatment‐naive and newly diagnosed Italian and Dutch subjects and 107 local controls. As with the study by Di Paola et al, this study used the Roche 454 pyrosequencing device.…”

“…A second organism that has emerged in these studies is the Ruminococcaceae family, which was increased in the ERA and in the polyarticular JIA patients in the Di Paola study as well as in the Italian patients in the van Dijkhuizen study . While this was not further speciated, one might speculate as to whether this was Ruminococcus gnavus , which was increased in two cohorts of patients with SpA and correlated with disease activity among those with concomitant inflammatory bowel diseases (IBD) .…”

“…To date, seven studies have evaluated the microbiota in children with JIA. [6][7][8]57,[91][92][93] One additional study 94 included children with JIA as controls for children with inflammatory bowel disease, but there was minimal data comparing the microbiota of the JIA patients to that of the healthy controls, so the study will not be discussed further.…”