Emerging epigenetic dynamics in gut-microglia brain axis: Experimental and clinical implications for accelerated brain aging in schizophrenia

dc.contributor.authorBen-Azu, Benneth
dc.contributor.authordel Re, Elisabetta C.
dc.contributor.authorVanderZwaag, Jared
dc.contributor.authorCarrier, Micaël
dc.contributor.authorKeshavan, Matcheri
dc.contributor.authorKhakpour, Mohammadparsa
dc.contributor.authorTremblay, Marie-Ève
dc.description.abstractBrain aging, which involves a progressive loss of neuronal functions, has been reported to be premature in probands affected by schizophrenia (SCZ). Evidence shows that SCZ and accelerated aging are linked to changes in epigenetic clocks. Recent cross-sectional magnetic resonance imaging analyses have uncovered reduced brain reserves and connectivity in patients with SCZ compared to typically aging individuals. These data may indicate early abnormalities of neuronal function following cyto-architectural alterations in SCZ. The current mechanistic knowledge on brain aging, epigenetic changes, and their neuropsychiatric disease association remains incomplete. With this review, we explore and summarize evidence that the dynamics of gut-resident bacteria can modulate molecular brain function and contribute to age-related neurodegenerative disorders. It is known that environmental factors such as mode of birth, dietary habits, stress, pollution, and infections can modulate the microbiota system to regulate intrinsic neuronal activity and brain reserves through the vagus nerve and enteric nervous system. Microbiota-derived molecules can trigger continuous activation of the microglial sensome, groups of receptors and proteins that permit microglia to remodel the brain neurochemistry based on complex environmental activities. This remodeling causes aberrant brain plasticity as early as fetal developmental stages, and after the onset of first-episode psychosis. In the central nervous system, microglia, the resident immune surveillance cells, are involved in neurogenesis, phagocytosis of synapses and neurological dysfunction. Here, we review recent emerging experimental and clinical evidence regarding the gut-brain microglia axis involvement in SCZ pathology and etiology, the hypothesis of brain reserve and accelerated aging induced by dietary habits, stress, pollution, infections, and other factors. We also include in our review the possibilities and consequences of gut dysbiosis activities on microglial function and dysfunction, together with the effects of antipsychotics on the gut microbiome: therapeutic and adverse effects, role of fecal microbiota transplant and psychobiotics on microglial sensomes, brain reserves and SCZ-derived accelerated aging. We end the review with suggestions that may be applicable to the clinical setting. For example, we propose that psychobiotics might contribute to antipsychotic-induced therapeutic benefits or adverse effects, as well as reduce the aging process through the gut-brain microglia axis. Overall, we hope that this review will help increase the understanding of SCZ pathogenesis as related to chronobiology and the gut microbiome, as well as reveal new concepts that will serve as novel treatment targets for SCZ.en_US
dc.description.sponsorshipThis research was supported by Canadian Institutes of Health Research (CIHR) and ERA-NET Neuron, Synaptic Dysfunction in Disorders of the Central Nervous System (MicroSynDep) grant awarded to M-ÈT. BB-A holds an International Brain Research Organization African Regional Committee (IBRO-ARC) 2019 Grant for a Post-Doctoral Fellowship at the University of Victoria. ER and MKe were recipients of the National Institute of Mental Health (MHI122759 and MH096942). JV holds a Canadian Graduate Scholarships–Master’s from CIHR and a Faculty of Graduate Studies (University of Victoria) Scholarship. M-ÈT holds a Canada Research Chairs (Tier II) in Neurobiology of Aging and Cognition. BB-A and M-ÈT were joint recipients of the Canadian-Israel Research grant (IDRC Project 109925) supported by the Canadian Institutes of Health Research (CIHR), the International Development Research Center (IDRC), the Israel Science Foundation (ISF), and the Azrieli Foundation.en_US
dc.identifier.citationBen-Azu, B., del Re, E. C., VanderZwaag, J., Carrier, M., Keshavan, M., Khakpour, M., & Tremblay, M-È. Emerging epigenetic dynamics in gut-microglia brain axis: Experimental and clinical implications for accelerated brain aging in schizophrenia. Frontiers in Cellular Neuroscience, 17, 1139357. https://doi.org/10.3389/fncel.2023.1139357en_US
dc.publisherFrontiers in Cellular Neuroscienceen_US
dc.subjectvagus nerveen_US
dc.titleEmerging epigenetic dynamics in gut-microglia brain axis: Experimental and clinical implications for accelerated brain aging in schizophreniaen_US


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