Gut virome in infants and young children developing islet autoimmunity

Objectives: The gut virome is an important component of the microbiome. It comprises human viruses including known candidates for triggering islet autoimmunity, as well as phages that interact with the gut bacteriome. The association between the gut virome and initiation of islet autoimmunity is elusive, as data are available only from two Finnish studies. Our aim was to assess the gut virome prior to the seroconversion of islet autoantibodies in the Norwegian birth cohort study MIDIA.Methods: We investigated series of stool samples covering the last year before the development of islet autoimmunity in 24 children with early-onset islet autoimmunity (9 - 24 months of age at the first of two or more islet antibodies). Each case subject was matched by place and season of birth to two controls carrying the identical high-risk HLA genotype. Viromes were characterized in 311 samples by metagenomic sequencing. Prevalent viruses were then tested in each sample by quantitative real-time (RT-) PCR. Generalized estimating equations were used for statistical analysis.Results: Neither of human viruses or bacteriophage genera was associated with islet autoimmunity: the most often detected taxa were parechovirus, enterovirus, bocaparvovirus, anellovirus, calicivirus. Of phages, CrAssphage was the most prevalent, followed by various genera of siphoviruses, podoviruses, myoviruses and microviruses. The virome diversity did not differ between cases and controls. Weak association signals originated from taxonomically unclassifiable motifs.Conclusions: Although the present study included the highest number so far of subjects with islet autoimmunity, and used rigorous matching, none of known human viruses or concrete phage taxa in human stool could be linked to islet autoimmunity. This is in accordance to what has been long known from earlier studies that tested individual viruses in stool. The study also demonstrated technical limitations of metagenomic sequencing as compared to rigorous quantitative PCR testing.