{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:28:02Z","timestamp":1792459682509,"version":"4.5.0"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The demyelination peak was characterized by reduced abundance of SCFA-producing genus\n                      <jats:italic>Akkermansia<\/jats:italic>\n                      and\n                      <jats:italic>Dubosiella<\/jats:italic>\n                      , 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\u03b2) 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-\u03b1, IL-1\u03b2, IL-6, IL-17) and only partially resolved, suggesting that a balanced inflammatory response may aid remyelination.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1682183","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:17:55Z","timestamp":1761628675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Intestinal mucosal alterations parallel central demyelination and remyelination: insights into the gut-brain axis in the cuprizone model of multiple 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