Post-Weaning Gut Microbiota Colonization Reveals Divergent Recovery of Skeletal Muscle and Peripheral Nerves
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Abstract We previously demonstrated that the absence of a complex gut microbiota (CGM) impairs the postnatal development of peripheral nerves and motor targets in germ-free (GF) mice. In this study, we investigated whether establishing a complex gut microbiota after weaning could reverse these developmental alterations. To address this question, GF mice were colonized with a complex gut microbiota by co-housing with conventionally raised mice. Microbiota composition, peripheral nerve morphology and transcriptional profiles, skeletal muscle proteome, neuromuscular junction architecture and circulating metabolites were comprehensively analyzed and compared with those of GF, gnotobiotic OMM12 and CGM mice. Post-weaning colonization partially restored microbial diversity and resulted in a compositionally distinct microbial community with reduced alpha diversity and enrichment of Duncaniella muris strain B8. Despite successful microbial colonization, peripheral nerve abnormalities persisted, including axon hypermyelination, transcriptional alterations in sciatic nerves, elongated nodes of Ranvier, and dysregulated axon-glia interactions. In contrast, skeletal muscle defects were largely rescued, with restoration of muscle mass, normalization of proteomic profiles, recovery of metabolic and structural pathways, and reduced fragmentation of the postsynaptic neuromuscular junction, although presynaptic abnormalities persisted. These findings demonstrate that microbiota-dependent developmental alterations differ markedly in their reversibility across the neuromuscular system. Specifically, post-weaning colonization with a complex gut microbiota resulted in broad recovery of skeletal muscle but failed to rescue peripheral nerve abnormalities. Our findings provide a framework for future studies investigating how the timing of microbial colonization, microbiota composition, and microbiota-derived signals influence the reversibility of microbiota-dependent neuromuscular alterations. Significance Statement The gut microbiota plays an essential role in neuromuscular development. However, it is largely unknown whether developmental alterations caused by its absence can be reversed. Using germ-free mice colonized with a complex microbiota after weaning, we demonstrate that the extent of recovery differs markedly across the neuromuscular system. Although skeletal muscle largely regains its structural and molecular features, abnormalities in the peripheral nerves persist despite successful microbial colonization. These findings show that microbiota-dependent developmental alterations are not equally reversible, pointing to the timing of microbial exposure and the availability of microbiota- derived signals as important variables. Our study provides a framework for identifying therapeutic windows and microbiota-derived signals that regulate neuromuscular development.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Post-Weaning Gut Microbiota Colonization Reveals Divergent Recovery of Skeletal Muscle and Peripheral Nerves
- Date Crossref
- 14/09/2026
- Éditeur
- openRxiv
- Type
- posted-content
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University of Padua pays non établi dans la noticeUniversité ou école supérieure
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Neuroscience Institute pays non établi dans la noticeStructure de recherche
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University of Turin pays non établi dans la noticeUniversité ou école supérieure
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Medizinische Hochschule Hannover pays non établi dans la noticeUniversité ou école supérieure
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University of Milan Department of Biomedical Sciences for Health pays non établi dans la noticeUniversité ou école supérieure
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Technical University of Munich pays non établi dans la noticeUniversité ou école supérieure
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Hannover Re (Germany) pays non établi dans la noticeEntreprise
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University of Padova Department of Molecular Medicine pays non établi dans la noticeUniversité ou école supérieure
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University of Torino Department of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO) pays non établi dans la noticeUniversité ou école supérieure
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Institute of Neuroanatomy and Cell Biology pays non établi dans la noticeStructure de recherche
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Research Core Unit Genomics pays non établi dans la noticeInstitution
University of Padua, Neuroscience Institute et University of Turin, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.