Gut Microbiome Dysbiosis and Increased Intestinal Permeability in Australian Children with Islet Autoimmunity and Type 1 Diabetes

We aimed to characterise the gut microbiome and small intestinal permeability in children with islet autoimmunity and type 1 diabetes (T1D). 88 participants, median age 11.8 (IQR 8.1-13.3) years at baseline were followed 6 monthly for a median of 13 months (range 2-34). 18 had islet autoimmunity, 29 recent-onset T1D, and 41 were age and gender-matched unrelated or sibling controls. Stool samples were collected (Omnigene kit) for 16S rRNA gene sequencing. Small intestinal permeability was measured by blood lactulose:rhamnose ratio (L/R), 90 minutes after drinking a 5gm lactulose/1gm rhamnose solution. Antibodies to insulin, GAD, IA2 and ZnT8 were assayed using IASP standardized radiobinding assays. Statistical analysis used linear mixed models. Differential abundance analysis used limma with total-sum scaling.

Children with islet autoimmunity or T1D had gut microbiome dysbiosis with reduced α diversity and different β diversity compared with controls. Progressors from islet autoimmunity to T1D had lower observed richness (OTUs) (p=0.01) and different β diversity (Adonis, P=0.004), compared with non-progressors. Genus Prevotella, with anti-inflammatory properties, was less abundant in children with T1D (p<0.005) or ≥ 2 islet antibodies (p<0.005) than in controls. Diet did not explain this difference. L/R was higher in T1D than sibling controls (mean difference +3.03±1.02, p=0.003). Progressors had higher L/R than non-progressors (+4.74±1.97, p=0.01) and sibling controls (+4.62±1.69, p=0.006). There was a trend towards a relationship between higher L/R and lower observed richness in the microbiome over time in children with ≥ 2 islet antibodies or T1D (coeff -0.0617, 95% CI -0.1254, 0.002 P=0.058).

Australian children progressing from islet autoimmunity to T1D have gut dysbiosis and increased intestinal permeability. This observation supports a mechanism underlying progression to T1D.