Background Type 1 Diabetes (T1D) is a severe autoimmune disease affecting the insulin-producing beta cells of the pancreas. T1D requires lifelong insulin treatment and is associated with increased mortality and morbidity. The cause is still unknown, but increasing incidence, clustering of new cases in space and time, seasonality and geographical differences suggest strong environmental influences. The genetic predisposition to T1D is mainly driven by the immune-related human leukocyte antigen (HLA) genes, where the HLA-DR3DQ2 and HLADR4DQ8 haplotypes confer the greatest risk. Clinical T1D can present at any age, often in early adolescence, but the autoimmune process driving the progressive loss of beta cells usually begins in early childhood. The gut microbiome is an important link between the environment and the immune system and is responsible for several metabolic and immunological functions. Different autoimmune disorders have been associated with alterations in microbiome composition and diversity, but the interaction between risk-associated HLA haplotypes, microbiome composition and T1D in the general population is still incompletely understood.

Objective The overall aim of this thesis was to identify factors associated with development of type 1 diabetes in a general population cohort, with focus on early childhood infections and the early gut microbiome.

Material and methodsThe All Babies In Southeast Sweden (ABIS) study is a prospective general population cohort followed from birth (1997-1999) to adulthood using questionnaires and biological samples. This thesis includes data from the birth (n=16 428), 1-year (n=11 093), 3-year (n=8 890) and 5-year questionnaires (n=7 445), blood samples sequenced for HLA haplotypes (n=3 947) and stool samples collected at 12 months of age (n=1 756). Logistic regression analyses and 16S rRNA sequencing were used to investigate the interaction between environmental exposures, microbiome composition and future T1D. As of December 2023, 168 individuals have been diagnosed with T1D according to the National Patient Register and validated by the National Drug Prescription Register.

Results Maternal respiratory tract infection in the first trimester of pregnancy and a high frequency of gastroenteritis in the 1-3-year age interval were associated with increased risk of T1D. Other types of infection or antibiotic treatments during pregnancy or early childhood were not associated with T1D in this general population cohort. Presence or absence of risk-associated HLA haplotypes had significant effects on gut microbiome composition at 12 months of age. T1D in individuals with a neutral or decreased genetic risk was associated with a higher frequency of both viral and bacterial infections in early childhood, while T1D individuals with increased risk reported fewer episodes of the common cold compared to healthy controls. The core gut microbiome of infants with a future T1D diagnosis (n=16) had taxonomical and functional differences compared to matched controls (n=268) at 12 months of age.

ConclusionsPerinatal or early childhood exposure to infections had a limited effect on the risk of developing T1D in this general population cohort. Individuals without risk-associated HLA haplotypes, possibly protected by a symbiotic (or “healthy”) microbiome, appear to require more environmental “triggers” to develop T1D compared to high-risk individuals. Differences in gut microbiome composition evident already at 12 months of age suggest that prevention of T1D requires modification of environmental influences in either pregnancy or infancy.