Microbiome-mitochondria crosstalk in neuro-oncology: molecular mechanisms, immunometabolic reprogramming, and therapeutic opportunities.

Although the gut microbiome is increasingly recognized as an important regulator of metabolic, immune, and neurophysiological functions, and mitochondrial dysfunction is considered a hallmark of metabolic flexibility, oxidative stress, and resistance to therapy in cancers, the role of microbiome-derived cues and mitochondrial processes in brain tumors remains poorly understood. The Microbiome-Gut-Brain-Mitochondria Axis in Neuro-Oncology provides a framework for understanding metabolism and immunity in neuro-oncology by highlighting this axis and emphasizing its role in glioblastoma. Metabolites produced by the microbiome, including short-chain fatty acids, bile acid metabolites, tryptophan metabolites, and other microbial compounds, have been shown to affect the immune system, barrier function, cellular metabolism, and neural signaling. Mitochondria are capable of functioning as intracellular communication mechanisms that will help to decipher those signals in order to create energy, ROS, calcium communication, biogenesis of mitochondria, quality control, and apoptosis. These processes may contribute to metabolic plasticity in glioblastomas, including glycolytic, oxidative phosphorylation, and amino- and lipid-metabolic adaptations, mitochondrial transfer, adaptation to hypoxia, tumor cell stemness, and immune suppression in the tumor microenvironment. The article also discusses the relationships between microbiome-derived cues, mitochondria, and tumor-associated immune populations. Microbiome-derived and mitochondrial biomarkers, combined with multi-omics approaches, single-cell technologies, spatial biology, artificial intelligence, and new experimental models, may help to identify relevant microbiome-mitochondria signatures. Modulating the microbiome, mitochondria, and combination therapies appears promising for glioblastomas. However, the causative link between microbiome-derived mitochondrial mechanisms and human brain tumors remains unproven. The necessity of prospective and mechanistic studies of the microbiome, mitochondria, metabolism, immunity, and clinical aspects arises.