Myelin as a regulator of development of the microbiota-gut-brain axis

Autor: Michael T. Hsieh, Mélanie G. Gareau, Ciara E. Keogh, Matteo M. Pusceddu, Mackenzie Honeycutt, Gonzalo Rabasa, Ingrid Brust-Mascher, Mariana Barboza, Danielle H.J. Kim, Trina A. Knotts, Jessica A. Sladek
Rok vydání: 2021
Předmět:
0301 basic medicine
medicine.medical_specialty
1.1 Normal biological development and functioning
Immunology
Gut–brain axis
Hippocampus
Butyrate
Neurodegenerative
Gut flora
Inbred C57BL
Autoimmune Disease
Mice
03 medical and health sciences
Behavioral Neuroscience
Myelin
0302 clinical medicine
Immune system
Underpinning research
Internal medicine
Behavioral and Social Science
Genetics
medicine
Psychology
Animals
Myelin Sheath
Pediatric
Neurology & Neurosurgery
biology
Endocrine and Autonomic Systems
Microbiota
Neurosciences
Brain
biology.organism_classification
medicine.disease
Phenotype
Brain Disorders
Anti-Bacterial Agents
Gastrointestinal Microbiome
Mice
Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Neurological
Digestive Diseases
Dysbiosis
030217 neurology & neurosurgery
Zdroj: Brain, Behavior, and Immunity. 91:437-450
ISSN: 0889-1591
DOI: 10.1016/j.bbi.2020.11.001
Popis: Myelination in the peripheral and central nervous systems is critical in regulating motor, sensory, and cognitive functions. As myelination occurs rapidly during early life, neonatal gut dysbiosis during early colonization can potentially alter proper myelination by dysregulating immune responses and neuronal differentiation. Despite common usage of antibiotics (Abx) in children, the impact of neonatal Abx-induced dysbiosis on the development of microbiota, gut, brain (MGB) axis, including myelination and behavior, is unknown. We hypothesized that neonatal Abx-induced dysbiosis dysregulates host-microbe interactions, impairing myelination in the brain, and altering the MGB axis. Neonatal C57BL/6 mice were orally gavaged daily with an Abx cocktail (neomycin, vancomycin, ampicillin) or water (vehicle) from postnatal day 7 (P7) until weaning (P23) to induce gut dysbiosis. Behavior (cognition; anxiety-like behavior), microbiota sequencing, and qPCR (ileum, colon, hippocampus and pre-frontal cortex [PFC]) were performed in adult mice (6–8 weeks). Neonatal Abx administration led to intestinal dysbiosis in adulthood, impaired intestinal physiology, coupled with perturbations of bacterial metabolites and behavioral alterations (cognitive deficits and anxiolytic behavior). Expression of myelin-related genes (Mag, Mog, Mbp, Mobp, Plp) and transcription factors (Sox10, Myrf) important for oligodendrocytes were significantly increased in the PFC region of Abx-treated mice. Increased myelination was confirmed by immunofluorescence imaging and western blot analysis, demonstrating increased expression of MBP, SOX10 and MYRF in neonatally Abx-treated mice compared to sham controls in adulthood. Finally, administration of the short chain fatty acid butyrate following completion of the Abx treatment restored intestinal physiology, behavior, and myelination impairments, suggesting a critical role for the gut microbiota in mediating these effects. Taken together, we identified a long-lasting impact of neonatal Abx administration on the MGB axis, specifically on myelin regulation in the PFC region, potentially contributing to impaired cognitive function and bacterial metabolites are effective in reversing this altered phenotype.
Databáze: OpenAIRE
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