Antibiotic-induced microbiome depletion in adult mice disrupts blood-brain barrier and facilitates brain infiltration of monocytes after bone-marrow transplantation

The crosstalk between intestinal bacteria and central nervous system, so called the gut-brain axis, is critically important for maintaining brain homeostasis and function. This study aimed to investigate integrity of blood-brain barrier (BBB) and migration of bone marrow (BM)-derived cells to brain parenchyma after intestinal microbiota depletion in adult mice. Gut microbiota dysbiosis was induced with 5 non-absorbable antibiotics in drinking water in mice that had received bone marrow transplantation (BMT) from green fluorescent protein (GFP) transgenic mice. Antibiotic-induced microbiome depletion reduced expression of tight-junction proteins of brain blood vessels and increased BBB permeability. Fecal microbiota transplantation of antibiotics treated mice with pathogen-free gut microbiota decreased BBB permeability and up-regulated expression of tight junction proteins. The BM-derived GFP+ cells were observed to infiltrate specific brain regions, including nucleus accumbens (NAc), septal nucleus (SPT) and hippocampus (CA3). The infiltrated cells acquired a ramified microglia-like morphology and Iba1, a microglia marker, was expressed in all GFP+ cells, whereas they were negative for astrocyte marker GFAP. Furthermore, treatment with CCR2 antagonist (RS102895) suppressed recruitment of BM-derived monocytes to brain. We report for first time migration of BM-derived monocytes to brain regions involved in regulating emotional behaviors after depletion of intestinal microbiota in BMT background mice. However, mechanisms responsible for migration and functions of microglia-like infiltrated cells in brain need further investigation. These findings indicate that monocyte recruitment to brain in response to gut microbiota dysbiosis may represent a novel cellular mechanism that contributes to development of brain disorders.