
Abstract Text:
Background: Traumatic brain injury (TBI) is the leading cause of death under the age 45 in the Western World and is followed by secondary brain damage leading to long-term consequences, such as increased prevalence of dementia, and Alzheimer’s disease (AD). Recent evidence suggested that both TBI and AD have an alteration in the brain-gut microbiota axis that may significantly contribute to their pathogenesis and could be the missed link to understand their association. Furthermore, accumulating evidences in literature have showed that the endocannabinoid (eCB) system with the accompanying “endocannabinoidome” (eCBome) have a key role in numerous physiological and pathological conditions, including neuroprotection. The endocannabinoidome is increasingly emerging as a system of lipid mediators of the health-disease continuum, and its strong connection with the gut microbiome has been so far suggested only in the context of inflammatory metabolic and intestinal disorders and has never been investigated in other disorders. Hypothesis: Based on published preclinical, clinical, and epidemiological data, we propose a theoretical framework that highlights the potential mechanisms by which the gut-brain axis and the connection with the eCBome may peripherally influence the physiopathology of TBI and the subsequent risk of latent neurodegenerative diseases. Specific Aims: Therefore, the objective of this research is to investigate the effects of a mild TBI on the subsequent development of AD-related neuropathology and cognitive impairments in an of amyloid precursor protein (APP)/PS1 mice, the role of inflammation, the potential perturbation of the gut microbiome and how the potential alteration in gut microbiota composition may determine the severity of these disorders by regulating the activity of endocannabinoid and related mediators. Research Strategy: We plan to analyze the microbiome of APP/PS1 mice after mild TBI and their healthy controls. Feces and intestinal tissues from these animals will be used to compare the taxonomic composition, genome, transcriptome, proteome, and metabolome of the gut microbiome. The endocannabinoidome will be profiled in the gut and in other target tissues, with particular emphasis on brain. Microbiome analyses will be related to the biochemical characterization of the endocannabinoidome in key target tissues. To accomplish this aim, we will take advantage to be part of the Joint International Research Unit (UMI) that is a bilateral research unit between the Italian National Research Council (CNR) and the Université Laval of Quebec that has among its proposed ambitious goals the development of research projects, and the innovation, education, and knowledge transfer in the emerging field of the biomolecular study of the intestinal microbiome. Innovation and Impact: This represents a unique opportunity to carry out this pilot study that could open new perspectives for the development of novel microbiome-based interventions for neurodegenerative diseases and to prevent long-term consequences of TBI.
Project Terms:
Age; Alzheimer’s Disease; Amyloid beta-Protein Precursor; animal tissue; base; Bilateral; Biochemical; Brain; Brain Injuries; Cause of Death; Clinical Data; Dementia; Development; Disease; Education; Endocannabinoids; endogenous cannabinoid system; epidemiologic data; Feces; Functional disorder; Genome; Goals; gut microbiome; gut microbiota; gut-brain axis; Health; Impaired cognition; Inflammation; Inflammatory; innovation; International; Intervention; Intestinal Diseases; Intestines; Joints; Knowledge; Link; lipid mediator; Literature; Mediator of activation protein; Metabolic Diseases; metabolome; microbiome; microbiome analysis; microbiota-gut-brain axis; mild traumatic brain injury; Mus; National Research Council; Neurodegenerative Disorders; neuropathology; neuroprotection; novel; Pathogenesis; Pathologic; Peripheral; Physiological; Pilot Projects; pre-clinical; Prevalence; prevent; Proteome; Publishing; Quebec; Research; research and development; Research Project Grants; Risk; Role; Severities; System; Taxonomy; Tissues; transcriptome; Traumatic Brain Injury; Western World