Autor(es):
Ferreira, Carolina ; Carvalho, Filipa ; Vieira, Pedro ; Alves, André ; Palavra, Filipe ; Almeida, Jani ; Alves, Vera ; Coscueta, Ezequiel ; Pereira, Patrícia Dias ; Pintado, Manuela ; Sá, Helena ; Castelo-Branco, Miguel ; Reis, Flávio ; Viana, Sofia
Data: 2025
Identificador Persistente: http://hdl.handle.net/10400.14/55547
Origem: Veritati - Repositório Institucional da Universidade Católica Portuguesa
Assunto(s): Cuprizone-induced demyelination; Gliosis; Gut-brain axis; Gut microbiota; Intestinal innate and adaptative immunity; Multiple sclerosis; Neuroinflammation; Remyelination
Descrição
Background: 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.
