Islet autoantibody seroconversion in type-1 diabetes is associated with metagenome-assembled genomes in infant gut microbiomes

Abstract

The immune system of some genetically susceptible children can be triggered by certain environmental factors to produce islet autoantibodies (IA) against pancreatic β cells, which greatly increases their risk for Type-1 diabetes. An environmental factor under active investigation is the gut microbiome due to its important role in immune system education. Here, we study gut metagenomes that are de-novo-assembled in 887 at-risk children in the Environmental Determinants of Diabetes in the Young (TEDDY) project. Our results reveal a small set of core protein families, present in >50% of the subjects, which account for 64% of the sequencing reads. Time-series binning generates 21,536 high-quality metagenome-assembled genomes (MAGs) from 883 species, including 176 species that hitherto have no MAG representation in previous comprehensive human microbiome surveys. IA seroconversion is positively associated with 2373 MAGs and negatively with 1549 MAGs. Comparative genomics analysis identifies lipopolysaccharides biosynthesis in Bacteroides MAGs and sulfate reduction in Anaerostipes MAGs as functional signatures of MAGs with positive IA-association. The functional signatures in the MAGs with negative IA-association include carbohydrate degradation in lactic acid bacteria MAGs and nitrate reduction in Escherichia MAGs. Overall, our results show a distinct set of gut microorganisms associated with IA seroconversion and uncovered the functional genomics signatures of these IA-associated microorganisms

Persistent Biofluid Small-Molecule Alterations Induced by Trypanosoma cruzi Infection Are Not Restored by Parasite Elimination

“…Generalized linear mixed model (GLMM) analysis was performed using the glmmTMB package (Version 1.1.2.3) in the R environment (version 3.6.2) . DPI and treatment groups (infected, uninfected, and isoproterenol treatment) were set as fixed effects, while the mouse ID was set as a random effect . The probability distribution and link function of the GLMM models were set to Gaussian and identity, respectively.…”

Possible heterogeneity of initial pancreatic islet beta‐cell autoimmunity heralding type 1 diabetes

“…Fungal taxa were not related to first islet autoantibodies [81]. Metagenome‐assembled genomes (MAGs) in 887 TEDDY children followed longitudinally revealed 883 species, including 176 previously undescribed human microbiome species [82]. Metagenome assemblies based on protein families were examined for association with the appearance of islet autoantibodies.…”

“…Metagenome assemblies based on protein families were examined for association with the appearance of islet autoantibodies. Results showed that 2373 MAGs were positively and 1549 negatively associated with IA[82]. A possible MAGs dichotomy of IAA‐and GADA first remains to be determined.…”

Pathophysiology of Type 1 Diabetes and Gut Microbiota Role

“…This evidence came from a Finnish study in which a reduction in microbiota richness was detected in children who develop T1D prior to diagnosis but after seroconversion [ 80 ]. Moreover, the seroconversion has been positively correlated with the increase of lipopolysaccharides biosynthesis in Bacteroides genome and sulfate reduction in Anaerostipes genome [ 81 ].…”