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Myelin as a regulator of development of the microbiota-gut-brain axis
Open accessAbstract
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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“The microbiota–gut–brain axis represents an important regulator of glial functions, making it an actionable target to ameliorate the development and progression of neurodegenerative diseases.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [62]
In the citing paper
“Notably, the gut microbiome has been shown to modulate oligodendrocyte maturation and myelin production.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [62]
In the citing paper
“Perturbations in gut microbiome, including GF conditions and antibiotic treatment, have been shown to trigger excessive myelination in the prefrontal cortex by inducing oligodendrocyte maturation and upregulating myelin-related genes.62,265”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [62]
In the citing paper
“Moreover, the administration of tributyrin, a prodrug of butyrate, rescued the myelin dysregulation and behavioral deficits in antibiotic-treated mice.62”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [62]
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Metadata
- Authors
- Keogh, C. E., Kim, D. H. J., Pusceddu, M. M., Knotts, T. A., Rabasa, G., Sladek, J. A., Hsieh, M. T., Honeycutt, M., Brust-Mascher, I., Barboza, M., & Gareau, M. G.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Gareau, Mélanie G.
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 91
- Pages
- 437-450
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC7749851
- OpenAlex
- W3097533391
- Cited by
- 137
- References
- 75
- Citations by year
- 2026: 24 · 2025: 31 · 2024: 35 · 2023: 23 · 2022: 13 · 2021: 11
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1 R01AT009365\u201001, U24-DK092993, SCR_015361)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- myelination, microbiota-gut-brain axis, neonatal antibiotic exposure, gut dysbiosis, oligodendrocyte development, SOX10, MYRF, myelin basic protein, prefrontal cortex, cognitive impairment, anxiety-like behavior, butyrate, short-chain fatty acids, bacterial metabolites, host-microbe interactions
- MeSH terms
- Gastrointestinal Microbiome, Animals, Anti-Bacterial Agents, Brain, Mice, Inbred C57BL, Myelin Sheath, Mice, Microbiota
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