Abstract
Simple SummaryIn the last few years, a lot of evidence demonstrated an unexpected bidirectional communication among the gut microbes and the brain. Gut microbiota derived molecules may affect the nervous system in physiological and pathological conditions, even modulating neurotransmitter levels. Here, we summarize the effects of neurotransmitters on the proliferation and differentiation of neuronal precursor cells in the adult brain, and in brain gliomas. Further, we discuss the hypothesis that modulation of neurotransmitters by gut microbiota might impact the development and progress of brain tumor, specifically glioma. Further investigation on the mechanisms involved in the bidirectional gut-brain communication is required to identify new molecular and cellular targets involved in the dysregulation of brain homeostasis occurring in glioma.Glioblastoma (GBM) is the most aggressive form of glioma tumor in adult brain. Among the numerous factors responsible for GBM cell proliferation and invasion, neurotransmitters such as dopamine, serotonin and glutamate can play key roles. Studies performed in mice housed in germ-free (GF) conditions demonstrated the relevance of the gut-brain axis in a number of physiological and pathological conditions. The gut–brain communication is made possible by vagal/nervous and blood/lymphatic routes and pave the way for reciprocal modulation of functions. The gut microbiota produces and consumes a wide range of molecules, including neurotransmitters (dopamine, norepinephrine, serotonin, gamma-aminobutyric acid [GABA], and glutamate) that reach their cellular targets through the bloodstream. Growing evidence in animals suggests that modulation of these neurotransmitters by the microbiota impacts host neurophysiology and behavior, and affects neural cell progenitors and glial cells, along with having effects on tumor cell growth. In this review we propose a new perspective connecting neurotransmitter modulation by gut microbiota to glioma progression.
Highlights
Glioma is the most common primary malignant tumor of the central nervous system (CNS) in adults, with 50% of patients showing the most aggressive form, glioblastoma (GBM) [1]
It is well accepted that the composition of gut microbiota can influence mood, behavior and cognition and that it synthesizes, modulates and responds to several neurotransmitters [3,4], which are deeply involved in those functions
In line with this result, a comprehensive study on GBM databases showed that expression of three GABA related genes—glutamate decarboxylase 1 (GAD1) and 2 (GAD2) and 4-aminobutyrate aminotransferase (ABAT)—are lower in mesenchymal GBM, indicating that a decreased production and possibly an increased catabolism may be linked to poor outcome [188]
Summary
Glioma is the most common primary malignant tumor of the central nervous system (CNS) in adults, with 50% of patients showing the most aggressive form, glioblastoma (GBM) [1]. Neurotransmitters act at synaptic level as chemical messengers allowing communication throughout the nervous system and with its effectors They play extra-synaptic roles mediating the proliferation and differentiation of neuronal progenitors in the stem cell niches of the brain. In this contest, neurotransmitters act as positive or negative inducers of neural cell proliferation, and similar activity have been reported on glioma cells. We report the evidence that gut microbiota produces, releases, and modulates neurotransmitter levels, and that these molecules play a role in regulation of the proliferation of neural progenitor and glioma cells. We highlight the need of further investigations on the interaction between gut-brain axis and glioma, in order to identify new targetable pathways as novel co-adjuvants of anti-glioma therapies
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