Post-Weaning Gut Microbiota Colonization Reveals Divergent Recovery of Skeletal Muscle and Peripheral Nerves
- 1Department of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Torino, Orbassano, 10043, (Torino), Italy
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.
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BibTeX
@misc{calabro2026postweaning,
title = {{Post-Weaning Gut Microbiota Colonization Reveals Divergent Recovery of Skeletal Muscle and Peripheral Nerves}},
author = {S. Calabro' and D. Pellegrino and C. Cicconetti and S. Kankowski and S. Farzin and F. Bertone and M. Fruhwein and F. Anselmi and D. Bizzotto and M. Basic and S. Bolsega and M. Steglich and L. Wiehlmann and C. Gelfi and D. Capitanio and K. Kleigrewe and S. Oliviero and G. Gambarotta and K. Haastert-Talini and M. Cescon and G. Ronchi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.747293},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.747293v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Post-Weaning Gut Microbiota Colonization Reveals Divergent Recovery of Skeletal Muscle and Peripheral Nerves
AU - S. Calabro'
AU - D. Pellegrino
AU - C. Cicconetti
AU - S. Kankowski
AU - S. Farzin
AU - F. Bertone
AU - M. Fruhwein
AU - F. Anselmi
AU - D. Bizzotto
AU - M. Basic
AU - S. Bolsega
AU - M. Steglich
AU - L. Wiehlmann
AU - C. Gelfi
AU - D. Capitanio
AU - K. Kleigrewe
AU - S. Oliviero
AU - G. Gambarotta
AU - K. Haastert-Talini
AU - M. Cescon
AU - G. Ronchi
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.747293
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.747293v1
AB - 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.
ER -