Intestinal Bacteroides drives glioma progression by regulating CD8+ T cell tumor infiltration

Changes in the gut microbiome can have profound effects on the nervous system through modulation of T cell and microglia function. Since our prior studies demonstrated that T cells and microglia positively regulate low-grade glioma growth through the establishment of T cell-microglia immune circuit, we sought to explore the impact of changes in the gut microbiota on tumor biology. For these studies, genetically engineered Neurofibromatosis type 1 (NF1) optic glioma (Nf1-OPG) mice were raised in a germ-free environment or treated with antibiotics to deplete gut bacteria. First, we demonstrated that Nf1-OPG mice raised in a germ-free (gnotobiotic) environment or treated with specific antibiotics lacked optic gliomas and had improved OPG-induced retinal pathology (increased retinal nerve fiber layer thickness). Second antibiotic-treated Nf1-OPG mice gavaged with fecal microbiota from Nf1-OPG mice raised in a standard barrier facility restored optic glioma growth. Third, we showed that both germ-free and antibiotic-treated Nf1-OPG mice exhibited reduced intra-tumoral CD8+ T cell content resulting from decreased microglia chemokine production. Collectively, these findings establish a mechanistic relationship between the gut microbiota and brain tumor growth relevant to potential therapeutic interventions for pediatric low-grade gliomas. All experiments were performed under active Animal Studies Committee protocols at Washington University School of Medicine(Washington University in St Louis Institutional Animal Care and Use Committee).Mice harboring a neomycin cassette insertion in exon 31 (Nf1+/-) with GFAP-Cre-mediated. Nf1 loss in neuroglial progenitors (Nf1flox/neo; GFAP-Cre, Nf1-OPG mice) (Bajenaru et al., 2003). Mice were either treated with Vancomycin or PBS from 6-12 weeks of age and optic nerves were harvested for single cell seq.