Early Life Environmental Risk Factors and Gut Microbiota in Juvenile Idiopathic Arthritis : - More than a gut feeling

Sammanfattning: Background: The autoimmune disease juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, but the cause is not fully established. Only a small percentage (13–18%) of the risk of contracting the disease can be attributed to genetic factors, but environmental factors are believed to be behind most of the risk. An unfavourable composition of gut bacteria has also been suggested as a factor that may increase the risk of developing JIA.  Aims: The main aim of this thesis was to study risk factors during fetal life and in the early childhood environment for future onset of JIA. A further aim was to study the composition and importance of the gut microbiota before the onset of JIA.  Methods: In the ABIS study, a population-based prospective birth cohort of 17,055 children, data were collected on environmental factors during pregnancy and childhood. We identified 111 individuals with a JIA diagnosis. Environmental factors were mainly analysed using multivariable logistic regression, with adjustment for confounding factors. The microbiome at one year of age was analysed from stool samples by 16S rRNA PCR.  Results: Significant associations could be noted between mode of birth, duration of breastfeeding, birth order and exposure to antibiotics or fish early in life with future onset of JIA. These risk factors were found to pose an even higher cumulative risk if several of the factors were present. Carrying a risk allele in combination with being exposed to a specific environmental factor further increased the risk. In addition, several taxa were identified in the gut microbiota at one year that were associated with future onset of JIA. Many of these taxa were associated with one or more of the identified early childhood environmental risk factors.  Conclusion: In these studies, it has been demonstrated that children with JIA have, very early in life, already been exposed to negative environmental factors (caesarean section, short-term breastfeeding, being firstborn and being exposed to antibiotics or fish during the first year of life). The effect from these risk factors appears to be to some extent mediated via a changed composition of the gut microbiota. An environmentally induced dysregulation of the microbiome can trigger or accelerate the development of JIA in genetically predisposed children.