Project description:Glioblastoma (GBM) is the most common and malignant brain tumor in adult humans. Recent studies have demonstrated a link between the composition of the gut microbiota and glioma progression. Here, we describe that the growth of glioma in mice is inversely correlated with the relative abundance of the anaerobic bacterium Muribaculum intestinale in the feces. We found that M. intestinale administration: 1) induced an inflammatory environment in the gut; 2) reduced glioma growth; 3) increased the pro-inflammatory profile of tumor-associated microglial cells and the frequency of CD8+ T cells; and 4) increased the peripheral TNF-α levels. The effects induced by M. intestinale administration were significantly reduced upon toll-like receptor 2 (TLR2) silencing using siRNA targeting TLR2. These receptors recognise microbial patterns and control immune responses to infection. Collectively, these data demonstrate that M. intestinale induces a pro-inflammatory response in glioma bearing mice, inhibiting tumor growth via TLR2-dependent signaling.
Project description:An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect identified Muribaculum intestinale as one of only two members with an oversized effect on T-cell populations. Here we report the identification and characterization of a lipid, MiCL-1, as the responsible metabolite. MiCL-1 is an 18:1-16:0 cardiolipin, whose close relatives are found on concave lipid surfaces of both mammals and bacteria. MiCL-1 was synthesized to confirm the structural analysis and functionally characterized in cell-based assays. It has a highly restrictive structure-activity profile, as its chain-switched analog fails to induce responses in any of our assays. MiCL-1 robustly induces the production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-23, but has no detectable effect on the anti-inflammatory cytokine IL-10. As is the case with other recently discovered immunomodulatory lipids, MiCL-1 requires functional TLR2 and TLR1 but not TLR6 in cell-based assays.
