Lactobacillus-derived indole-3-lactic acid suppresses meningioma malignant phenotypes by direct anti-proliferative effects and macrophage reprogramming.

BACKGROUND: The intratumoral microbiome influences cancer progression, but its role in meningiomas is unknown. We characterized the meningioma intratumoral microbiome and investigated its functional significance.

METHODS: 16 S rRNA sequencing was performed on 80 meningioma specimens (44 benign, 36 non-benign). Microbial findings were validated via fluorescence in situ hybridization (FISH) and transmission electron microscopy. Among differentially abundant genera, Lactobacillus was identified as the core genus due to its 100% detection rate and significant enrichment in benign tumors, and was thus selected for functional interrogation. We employed in vitro assays (proliferation, migration), non-targeted metabolomics, RNA sequencing, and co-culture systems with primary human macrophages derived from peripheral blood mononuclear cells (PBMCs) and THP-1 cells to dissect microbial-metabolite-immune interactions.

RESULTS: Meningiomas harbor a distinct intratumoral microbiome dominated by Firmicutes and Bacteroidota, with beta diversity revealing significant compositional differences between benign and non-benign tumors. The Lactobacillus genus was identified as a core genus enriched in benign tumors, and its abundance negatively correlated with the Ki-67 proliferation index. Logistic regression analysis further indicated an association between Lactobacillus abundance and low-aggressiveness tumor phenotypes (benign histology and low Ki-67 index); however, this association was not independent after adjusting for key clinical confounders. Functionally, the supernatant from cultured Lactobacillus intestinalis (putative L. intestinalis, a species belonging to the Lactobacillus genus that showed a differential abundance pattern between benign and non-benign meningiomas) suppressed IOMM-Lee cell proliferation and migration. Non-targeted metabolomics identified indole-3-lactic acid (ILA) and niacin as the predominant metabolites in the bacterial supernatant. ILA was established as the primary effector, recapitulating the direct antitumor effects and skewing human macrophages towards an M1-polarized phenotype with enhanced secretion of IL-12 and IL-6. While niacin also promoted M1 cytokine secretion, it lacked direct antiproliferative activity. Transcriptomic profiling of ILA-treated tumor cells confirmed the suppression of multiple oncogenic pathways.

CONCLUSION: This study characterizes the intratumoral microbiome of meningiomas and reveals that the Lactobacillus genus may serve as a potential microbial marker for a low-proliferation, low-necrosis tumor microenvironment. Furthermore, we uncover a tumor-suppressive mechanism mediated by Lactobacillus, identifying its metabolite, indole-3-lactic acid (ILA), as a key effector. As an exogenous compound, ILA exerts dual anti-tumor activity through direct anti-proliferative effects and immunomodulation in vitro experiments. While these findings are preliminary and require further validation in vivo, they suggest ILA as a potential preclinical candidate for informing future therapeutic strategies.