Abstract Body: Introduction: Gestational Diabetes Mellitus (GD) occurs when a woman without previously diagnosed diabetes develops chronic hyperglycemia during pregnancy. In the U.S., GD affects ~2-10% of women and has been linked to congenital anomalies and long-term risk in offspring. Recently shown that GD affects maternal microbiome, leading to dysbiosis, which has been linked to fetal neurodevelopmental-disorders. Although advancements in GD treatments, such as metformin, have improved outcomes, the effects of these treatments on long-term neurocognitive outcomes in offspring and in dam remain insufficiently studied.
Objective: GD-induced gut dysbiosis in pregnant mothers may lead to cognitive impairment with increased risk for neurological diseases in both the mother and offspring as they age, and reversing this dysbiosis could improve cognitive outcomes in both dams and offspring.
Methods: We utilized 3-month-old female C57BL/6J mice for our study and confirmed pregnancy prior to study. On gestational day 7, we injected Streptozotocin (STZ) to induce pancreatic dysfunction, creating a GD mouse model.
Results: We observed significant decrease in body weight and blood glucose levels in GD compared to control dams. H&E staining of pancreas showed morphological changes in beta cells, increased vacuolar swelling and increased apoptotic beta-cell loss, pancreatic qPCR analysis showed elevated proinflammatory cytokine IL-6, f-IHC in the brain indicated elevated GLUT3 signaling colocalized with morphological changes in astroglia of GD mice. f-IHC showed decreased ileal E-cadherin expression in GD mice, highlighting the impact of hyperglycemia on gut barrier integrity. Metabolomic analysis revealed significant reduction in tryptophan-metabolites in GD mice. Intestinal bacterial analysis demonstrated a reduction in the Actinobacteria phylum, with significant dysbiosis observed in GD compared to dams. Behavioral analyses, using Y-maze revealed significant (p<0.001) cognitive impairment, with significant differences (p<0.05) in anxiety phenotype analyzed by nest-building behavior in GD compared to control dams. These findings suggest a depressive phenotype and decrease cognitive performance observed in GD dams. Metformin did not rescue this phenotype in both dams and offspring born to GD dams.
Conclusion: Reversing dysbiosis could potentially rescue the maternal dysbiotic microbiome, reduce inflammation, and improve long-term neurocognitive outcomes in both dams and offspring.