Maternal antibiotic treatment enhances embryonic neogenesis of pancreatic islets with disease preventative effects in non-obese diabetic mice

The early intestinal microbiota is involved in the pathogenesis of type 1 diabetes. Antibiotic treatment during early developmental stages of gestation and postnatal life induces significant shifts in the immune system and susceptibility to destruction of islet beta cells in genetically prone rodent models for type 1 diabetes. Less focus has been on the environmental impact that gestational antibiotics may have on pancreatic embryogenesis and functional stage of beta cells later in life, and its potential role in disease progression. Our aim was to determine whether depletion of maternal microbiota during pregnancy was sufficient to change islet neogenesis and function in non obese diabetic mice. Exposure to ampicillin, vancomycin and neomycin during gestation depleted the maternal microbiome, and perturbed the normal gut colonization trajectory in the pups. The treatment enriched Akkermansia, and Rikenellacea in the 4 and 13 weeks old pups, respectively, and Bacteroides never colonized the gut as in the untreated pups. The gestational antibiotic treatment furthermore reduced fasting blood glucose in the mothers, reduced the weight of the pups until weaning, and reduced HbA1c levels and insulitis in the 13 weeks old pups. Interestingly, the alleviated phenotype in the antibiotic treated NOD mice was preceded by more than 50 perc. increase in total islet number and volume as well as increased insulin levels in the 2 weeks old pups. The islet mass expansion was not associated with any change in oral glucose tolerance in the prediabetic mice at 8 weeks of age. Also, only minimal long-term changes in serum IL 10 level and NKT cell, but not FoxP3 regulatory T cell, population were observed in the prenatally treated adult NOD mice. Our study highlights the importance of considering environmental factors involved in fetal programming of islet embryogenesis as determinants of the islet maturation process and functional state early in life that may define the risk for autoimmune destruction later in life