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Intestinal mucosal alterations parallel central demyelination and remyelination: insights into the gut-brain axis in the cuprizone model of multiple sclerosis

2025-10-28Artigo de investigação Acesso aberto
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dc.contributor.authorFerreira, Carolina
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorVieira, Pedro
dc.contributor.authorAlves, André
dc.contributor.authorPalavra, Filipe
dc.contributor.authorAlmeida, Jani
dc.contributor.authorAlves, Vera
dc.contributor.authorCoscueta, Ezequiel
dc.contributor.authorPereira, Patrícia Dias
dc.contributor.authorPintado, Manuela
dc.contributor.authorSá, Helena
dc.contributor.authorCastelo-Branco, Miguel
dc.contributor.authorReis, Flávio
dc.contributor.authorViana, Sofia
dc.date.accessioned2025-11-07T14:34:35Z
dc.date.available2025-11-07T14:34:35Z
dc.date.issued2025-10-28
dc.description.abstractBackground: The gut-brain axis has been increasingly recognized as a critical factor in Multiple Sclerosis (MS) pathophysiology. While its role in demyelination is well documented, gut-brain axis involvement during remyelination remains largely unexplored. Methods: Using the cuprizone (CPZ) model, which induces reversible demyelination and spontaneous remyelination upon toxin withdrawal, we investigated gut and brain changes during both disease stages in C57BL/6 mice. Animals were administered 0.2% cuprizone for 5 weeks to induce demyelination, followed by a 2-week recovery phase. Intestinal changes were evaluated through 1) gut microbiota profiling and metabolite production (short-chain fatty acids (SCFAs), indoxyl sulfate), 2) structural and barrier integrity via histology, mucus staining, and tight junction markers (ZO-1, occludin, claudin-5), 3) mucosal immunity through M1/M2 macrophage profiling and Th17/Treg ratios, and 4) expression of inflammatory and oxidative stress markers. Differences in brain demyelination/remyelination, gliosis and related molecular changes were determined using immunohistochemistry and real-time polymerase chain reaction (RT-PCR). Results: The demyelination peak was characterized by reduced abundance of SCFA-producing genus Akkermansia and Dubosiella, increased intestinal permeability at the level of the mucus layer and tight junction networks, and shifts in mucosal immunity toward a pro-inflammatory state characterized by M1 macrophages and Th17 cell expansion together with elevated levels of inflammatory cytokines (IL-17, IL-1?) and changes in oxidative stress-related enzymes (iNOS, HO-1, SOD1/2), all of which were partially reversed during the remyelination phase. Centrally, cuprizone-induced demyelination/remyelination and gliosis showed region-specific patterns. Neuroinflammation peaked during demyelination (TNF-?, IL-1?, IL-6, IL-17) and only partially resolved, suggesting that a balanced inflammatory response may aid remyelination. Conclusion: Our findings reveal that cuprizone-induced intestinal dysfunctions temporally parallel central nervous system (CNS) lesion dynamics, disclosing temporal coordination of both compartments and highlighting gut-brain axis impact on both disease stages.eng
dc.identifier.citationFerreira, C., Carvalho, F., Vieira, P., & Alves, A. et al. (2025). Intestinal mucosal alterations parallel central demyelination and remyelination: insights into the gut-brain axis in the cuprizone model of multiple sclerosis. Frontiers in Immunology, 16, Article 1682183. https://doi.org/10.3389/fimmu.2025.1682183
dc.identifier.doi10.3389/fimmu.2025.1682183
dc.identifier.eid105021537631
dc.identifier.issn1664-3224
dc.identifier.other64b854ee-3cc9-4111-b73e-9a507e01cd17
dc.identifier.pmid41229423
dc.identifier.urihttp://hdl.handle.net/10400.14/55547
dc.identifier.wos001610607200001
dc.language.isoeng
dc.peerreviewedyes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCuprizone-induced demyelination
dc.subjectGliosis
dc.subjectGut-brain axis
dc.subjectGut microbiota
dc.subjectIntestinal innate and adaptative immunity
dc.subjectMultiple sclerosis
dc.subjectNeuroinflammation
dc.subjectRemyelination
dc.titleIntestinal mucosal alterations parallel central demyelination and remyelination: insights into the gut-brain axis in the cuprizone model of multiple sclerosiseng
dc.typeresearch article
dspace.entity.typePublication
oaire.citation.titleFrontiers in Immunology
oaire.citation.volume16
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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