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.

中文翻译：

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抗生素诱导的成年小鼠微生物组耗竭破坏血脑屏障并促进骨髓移植后单核细胞的脑浸润

肠道细菌与中枢神经系统之间的串扰，即所谓的“肠-脑轴”，对于维持大脑稳态和功能至关重要。本研究旨在研究成年小鼠肠道微生物群耗竭后血脑屏障 (BBB) 的完整性和骨髓 (BM) 衍生细胞向脑实质的迁移。在从绿色荧光蛋白 (GFP) 转基因小鼠接受骨髓移植 (BMT) 的小鼠的饮用水中，用 5 种不可吸收的抗生素诱导肠道微生物群失调。抗生素诱导的微生物组耗竭降低了脑血管紧密连接蛋白的表达并增加了 BBB 通透性。抗生素治疗小鼠的粪便微生物群移植无病原体肠道微生物群降低 BBB 通透性并上调紧密连接蛋白的表达。观察到 BM 衍生的 GFP+ 细胞渗入特定的大脑区域，包括伏隔核 (NAc)、间隔核 (SPT) 和海马 (CA3)。浸润的细胞获得了分叉的小胶质细胞样形态，小胶质细胞标记物 Iba1 在所有 GFP+ 细胞中表达，而它们对星形胶质细胞标记物 GFAP 呈阴性。此外，用 CCR2 拮抗剂 (RS102895) 治疗抑制了 BM 衍生的单核细胞向大脑的募集。我们首次报告了在 BMT 背景小鼠肠道微生物群耗尽后，BM 衍生的单核细胞迁移到参与调节情绪行为的大脑区域。然而，负责大脑中小胶质细胞样浸润细胞迁移和功能的机制需要进一步研究。这些发现表明，响应肠道微生物群失调的单核细胞募集到大脑可能代表了一种新的细胞机制，有助于大脑疾病的发展。