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

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

  • Brain Behav Immun. 2021 Feb;92:102-114. doi: 10.1016/j.bbi.2020.11.032.
Nannan Sun 1,  Huiling Hu 2,  Fei Wang 2,  Lanlan Li 2,  Wanwan Zhu 2,  Yan Shen 3,  Jianbo Xiu 4,  Qi Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China; Center for Brian Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China.
  • 2 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 3 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
  • 4 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China. Electronic address: xiujianbo@ibms.cams.cn.
  • 5 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China. Electronic address: xuqi@pumc.edu.cn.
PMID: 33242652 DOI: 10.1016/j.bbi.2020.11.032
Abstract

The crosstalk between intestinal bacteria and the central nervous system, so called "the gut-brain axis", is critically important for maintaining brain homeostasis and function. This study aimed to investigate the integrity of the blood-brain barrier (BBB) and migration of bone marrow (BM)-derived cells to the 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 the 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 the expression of tight junction proteins. The BM-derived GFP+ cells were observed to infiltrate specific brain regions, including the nucleus accumbens (NAc), the septal nucleus (SPT) and the 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 the astrocyte marker GFAP. Furthermore, treatment with CCR2 Antagonist (RS102895) suppressed the recruitment of BM-derived monocytes to the brain. We report for the first time the migration of BM-derived monocytes to the brain regions involved in regulating emotional behaviors after depletion of intestinal microbiota in BMT background mice. However, mechanisms responsible for the migration and functions of the microglia-like infiltrated cells in the brain need further investigation. These findings indicate that monocyte recruitment to the brain in response to gut microbiota dysbiosis may represent a novel cellular mechanism that contributes to the development of brain disorders.

Keywords

Antibiotic; Blood-brain barrier; Bone marrow transplantation; Hippocampus; Microbiota; Monocytes; Nucleus accumbens; Septal nucleus.

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