Gut microbiome dysbiosis and increased intestinal permeability in Australian children with islet autoimmunity and type 1 diabetes

Background : Intestinal epithelial integrity reflects a healthy gut microbiome and both may be compromised in type 1 diabetes (T1D). We aimed to characterise the gut microbiome, bacterial products and small intestinal permeability longitudinally in children with islet autoimmunity (IA) .

Methods : 88 children, median age 11.8 (IQR 8.1-13.3) years, were followed 6-monthly for a median of 13 (range 2-34) months. 18 had IA, 29 recent-onset T1D, and 41 were age- and gender-matched unrelated or sibling controls. Stool samples were collected into Omnigene OMR-200 tubes for 16S rRNA gene sequencing. Small intestinal permeability was measured by blood lactulose:rhamnose ratio (L/R), 90 minutes after drinking 5% lactulose/1% rhamnose solution. Short chain fatty acids (SCFA) were measured by gas chromatography. Diet was assessed with the Australian Child and Adolescent Food Frequency Questionnaire.

Results : Children with IA or T1D had differences in ? diversity and reduced anti-inflammatory bacteria. The Prevotella genus was less abundant in children with ? 2 islet antibodies (p<0.005) or T1D (p<0.005). Dietary fibre intake did not differ. T1D had higher L/R than sibling controls [mean difference (SE) = +2.58 (1.14); p=0.02]. Children with ? 2 autoantibodies who progressed to T1D (progressors) had lower ? diversity (observed richness) [-27.9 (11.9) mean difference (SE) p=0.02], different ? diversity (Adonis p=0.004), and higher L/R  than non-progressors [+7.18 (2.38) mean difference (SE) p=0.003].  Lower ? diversity related weakly to higher L/R in all groups [regression coefficient -0.09 (0.02) p; -0.13 (0.06) p=0.03 (InvSimpson)]. Lower observed richness also related to lower plasma acetate (regression coefficient 0.5 (0.23) p =0.03), but plasma acetate did not differ between T1D or ? 2 islet autoantibody and controls.

Conclusion : Children with IA or T1D have gut dysbiosis and increased intestinal permeability. Progressors from IA to T1D have gut dysbiosis and increased intestinal permeability compared with non-progressors.