Role of gut microbiota in homeostatic maintenance and promoting regeneration of radiosensitive tissues in mice following radiation exposure

Abstract

Objective To investigate the role of gut microbiota (GM) in maintaining hematopoietic function and intestinal epithelial homeostasis function and promoting regeneration of hematopoietic tissues and intestinal epithelium in mice radiation exposure. Methods C57BL/6J mice (6~8 weeks) were treated with antibiotics added in drinking water for 21 d to deplete the GM (Abx group), and the control mice were given normal drinking water. The changes in body weight and general condition of the mice were recorded. The effect of GM depletion on hematopoietic homeostasis was evaluated by peripheral blood analysis and HE staining of the bone marrow, and the changes in intestinal homeostasis were determined with HE staining, BrdU immunohistochemistry, RT-qPCR, and enteroid culture. The mice with or without GM depletion were subjected to X-ray exposure at the total body irradiation (TBI) dose of 8 Gy, and the regeneration of the radiosensitive tissues were assessed at 3 and 7 d after the exposure. Results GM depletion induced by 21-day treatment with antibiotics resulted in severe weight loss of the mice (P < 0.01) and significant changes in peripheral white blood cells (WBC), red blood cells (RBC), hemoglobin and platelets, and markedly increased number of megakaryocytes in the bone marrow (P < 0.01). GM depletion induced an obvious decrease in crypt depth and the number of BrdU+ cryptal cells and significantly down-regulated the expression of intestinal stem cell-related genes including Lgr5, Olfm4, and Axin2. The mice with GM depletion showed significantly lowered enteroid formation capacity (P < 0.05) and shortened survival (P < 0.01) with obviously lowered rate of hematopoietic and intestinal tissue regeneration after radiation exposure. At 7 d after the radiation, the mice with GM depletion showed increased villous goblet cells and decreased cryptal enteroendocrine cells in the intestines. Conclusion Normally functioning GM are essential for maintaining hematopoietic and intestinal stem cell homeostasis and promoting regeneration of the radiosensitive tissues after radiation exposure.

Keywords

• gut microbiota
• intestinal stem cells
• hematopoiesis
• radiation injury
• repair and regeneration