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Myelin as a regulator of development of the microbiota-gut-brain axis.
Authors Keogh CE, Kim DHJ, Pusceddu MM, Knotts TA, Rabasa G, Sladek JA, Hsieh MT,
Honeycutt M, Brust-Mascher I, Barboza M, Gareau MG
Submitted By Submitted Externally on 2/22/2021
Status Published
Journal Brain, behavior, and immunity
Year 2021
Date Published 1/1/2021
Volume : Pages 91 : 437 - 450
PubMed Reference 33157256
Abstract 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.


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