SummaryBackgroundThe etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk.MethodsData was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n = 17,055), 111 of whom later acquired JIA (ABISJIA). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed.FindingsABISJIAhad higher abundance ofAcidaminococcales, Prevotella 9, andVeillonella parvulaand lower abundance ofCoprococcus,Subdoligranulum,Phascolarctobacterium,Dialisterspp.,Bifidobacterium breve,Fusicatenibacter saccharivorans,Roseburia intestinalis, andAkkermansia muciniphila(q’s < 0.05).Parabacteroides distasonisgreatly increased the odds of later contracting JIA (OR = 6.7; 1.81–24.84, p = 0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition.InterpretationMicrobial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis.Funding10.13039/501100004973Barndiabetesfonden;10.13039/501100001861Swedish Council for Working Life and Social Research;10.13039/501100004359Swedish Research Council;Östgöta Brandstodsbolag;10.13039/501100000265Medical Research Councilof Southeast Sweden;JDRF-Wallenberg Foundation;Linköping.