Gut microbiota alterations affect glioma growth and innate immune cells involved in tumor immunosurveillance in mice.

Glioma is a CNS tumor with few therapeutic options. Recently, host microbiota has been involved in the immune modulation of different tumors, but no data are available on the possible effects of the gut-immune axis on brain tumors. Here, we investigated the effect of gut microbiota alteration in a syngeneic (GL261) mouse model of glioma, treating mice with two antibiotics (ABX) and evaluating the effects on tumor growth, microbe composition, natural killer (NK) cells and microglia phenotype. We report that ABX treatment (i) altered the intestinal microbiota at family level, (ii) reduced cytotoxic NK cell subsets, and (iii) altered the expression of inflammatory and homeostatic proteins in microglia. All these findings could contribute to the increased growth of intracranial glioma that was observed after ABX treatment. These results demonstrate that chronic ABX administration alters microbiota composition and contributes to modulate brain immune state paving the way to glioma growth.

Nose-to-brain selective drug delivery to glioma via ferritin-based nanovectors reduces tumor growth and improves survival rate.

Gliomas are among the most fatal tumors, and the available therapeutic options are very limited. Additionally, the blood-brain barrier (BBB) prevents most drugs from entering the brain. We designed and produced a ferritin-based stimuli-sensitive nanocarrier with high biocompatibility and water solubility. It can incorporate high amounts of the potent topoisomerase 1 inhibitor Genz-644282. Here, we show that this nanocarrier, named The-0504, can cross the BBB and specifically deliver the payload to gliomas that express high amounts of the ferritin/transferrin receptor TfR1 (CD71). Intranasal or intravenous administration of The-0504 both reduce tumor growth and improve the survival rate of glioma-bearing mice. However, nose-to-brain administration is a simpler and less invasive route that may spare most of the healthy tissues compared to intravenous injections. For this reason, the data reported here could pave the way towards a new, safe, and direct ferritin-based drug delivery method for brain diseases, especially brain tumors.

Microglial cells: Sensors for neuronal activity and microbiota-derived molecules.

Microglial cells play pleiotropic homeostatic activities in the brain, during development and in adulthood. Microglia regulate synaptic activity and maturation, and continuously patrol brain parenchyma monitoring for and reacting to eventual alterations or damages. In the last two decades microglia were given a central role as an indicator to monitor the inflammatory state of brain parenchyma. However, the recent introduction of single cell scRNA analyses in several studies on the functional role of microglia, revealed a not-negligible spatio-temporal heterogeneity of microglial cell populations in the brain, both during healthy and in pathological conditions. Furthermore, the recent advances in the knowledge of the mechanisms involved in the modulation of cerebral activity induced by gut microbe-derived molecules open new perspectives for deciphering the role of microglial cells as possible mediators of these interactions. The aim of this review is to summarize the most recent studies correlating gut-derived molecules and vagal stimulation, as well as dysbiotic events, to alteration of brain functioning, and the contribution of microglial cells.

Short-chain fatty acids promote the effect of environmental signals on the gut microbiome and metabolome in mice.

Gut microorganisms and the products of their metabolism thoroughly affect host brain development, function and behavior. Since alterations of brain plasticity and cognition have been demonstrated upon motor, sensorial and social enrichment of the housing conditions, we hypothesized that gut microbiota and metabolome could be altered by environmental stimuli, providing part of the missing link among environmental signals and brain effects. In this preliminary study, metagenomic and metabolomic analyses of mice housed in different environmental conditions, standard and enriched, identify environment-specific microbial communities and metabolic profiles. We show that mice housed in an enriched environment have distinctive microbiota composition with a reduction in gut bacterial richness and biodiversity and are characterized by a metabolomic fingerprint with the increase of formate and acetate and the decrease of bile salts. We demonstrate that mice treated with a mixture of formate and acetate recapitulate some of the brain plasticity effects modulated by environmental enrichment, such as hippocampal neurogenesis, neurotrophin production, short-term plasticity and cognitive behaviors, that can be further exploited to decipher the mechanisms involved in experience-dependent brain plasticity.

Correction to: Impaired adult neurogenesis is an early event in Alzheimer's disease neurodegeneration, mediated by intracellular Aß oligomers.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Impaired adult neurogenesis is an early event in Alzheimer's disease neurodegeneration, mediated by intracellular Aß oligomers.

Alterations of adult neurogenesis have been reported in several Alzheimer's disease (AD) animal models and human brains, while defects in this process at presymptomatic/early stages of AD have not been explored yet. To address this, we investigated potential neurogenesis defects in Tg2576 transgenic mice at 1.5 months of age, a prodromal asymptomatic age in terms of Aß accumulation and neurodegeneration. We observe that Tg2576 resident and SVZ-derived adult neural stem cells (aNSCs) proliferate significantly less. Further, they fail to terminally differentiate into mature neurons due to pathological, tau-mediated, and microtubule hyperstabilization. Olfactory bulb neurogenesis is also strongly reduced, confirming the neurogenic defect in vivo. We find that this phenotype depends on the formation and accumulation of intracellular A-beta oligomers (AßOs) in aNSCs. Indeed, impaired neurogenesis of Tg2576 progenitors is remarkably rescued both in vitro and in vivo by the expression of a conformation-specific anti-AßOs intrabody (scFvA13-KDEL), which selectively interferes with the intracellular generation of AßOs in the endoplasmic reticulum (ER). Altogether, our results demonstrate that SVZ neurogenesis is impaired already at a presymptomatic stage of AD and is caused by endogenously generated intracellular AßOs in the ER of aNSCs. From a translational point of view, impaired SVZ neurogenesis may represent a novel biomarker for AD early diagnosis, in association to other biomarkers. Further, this study validates intracellular Aß oligomers as a promising therapeutic target and prospects anti-AßOs scFvA13-KDEL intrabody as an effective tool for AD treatment.