Gut microbiota translocation contributes to early islet apoptosis in streptozotocin-induced diabetes

Dysbiosis of the gut microbiota and impaired intestinal barrier are associated with diabetes development. The translocation of gut microbiota induced by streptozotocin (STZ) has been confirmed to damage pancreatic islets. However, it remains uncertain whether dysregulated gut microbiota plays an essential role in the translocation leading to pancreatic injury. In specific pathogen-free (SPF) and germ-free (GF) mice treated with STZ, we measured Glucose Metabolism levels, pancreatic islet damage, intestinal barrier integrity, and Bacterial content in the Pancreas to investigate the role of gut microbiota translocation in diabetes development. Shotgun metagenomic Sequencing was used to analyze the impact of STZ on gut microbiota structure and function. Fecal microbiota transplantation was performed to explore if gut microbiota translocation depends on STZ-induced structural dysregulation. STZ induced intestinal damage in SPF mice, resulting in gut microbiota translocation to the Pancreas, pancreatic Apoptosis, and dysregulated Glucose Metabolism. Despite inherent intestinal barrier damage, absence of pancreatic Apoptosis in GF mice further indicates that gut microbiota translocation is an essential prerequisite for STZ-induced pancreatic islet Apoptosis. STZ significantly altered mouse gut microbiota composition and function. Transplantation of fecal microbiota from STZ-treated or saline-treated mice into STZ-induced GF mice also resulted in microbial translocation and pancreas Apoptosis. Apoptosis of β cells in STZ-treated mice results from gut microbiota translocating to the Pancreas through impaired intestinal barrier caused by STZ treatment independent of alterations in the gut microbial community.IMPORTANCEIn our study, the Apoptosis of β cells in STZ-treated mice is the result of the translocation of gut microbiota to the Pancreas through the impaired intestinal barrier induced by STZ, independent of alterations in the gut microbiota. These findings proposed the potential role of compounds in impairing the intestinal barrier integrity, promoting microbiota migration and finally damaging pancreatic islets.