{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:29:01Z","timestamp":1791538141699,"version":"4.3.4"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, closely associated with neuroinflammation, immune dysregulation, and gut microbiota imbalance. Gut microbiota\u2010derived metabolites may modulate key targets involved in MS pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study integrated network pharmacology, machine learning (ML), and single\u2010cell transcriptome analysis to identify MS\u2010related differentially expressed genes (DEGs) and potential targets of gut microbial metabolites. Feature contributions were evaluated using the SHapley Additive exPlanations (SHAP) method, and causal relationships were validated via Mendelian randomization (MR). Single\u2010cell analysis, molecular docking, and assessments of drug\u2010likeness and toxicity were also performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Caspase\u20103 (CASP3) was identified as a core target interacting with multiple gut microbial metabolites, including L\u2010isoleucine, aromatic lactic acid derivatives, 3\u2010hydroxyphenethyl alcohol, and D\u2010xylose, potentially regulating neuroimmune responses via TNF, MAPK, IL\u201017, and galectin pathways. Specific microbial taxa, such as\n                      <jats:italic>Akkermansia<\/jats:italic>\n                      ,\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      , and\n                      <jats:italic>Bifidobacterium<\/jats:italic>\n                      , were closely associated with these metabolites. The metabolites exhibited favorable drug\u2010likeness and low predicted toxicity, indicating potential therapeutic value.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Gut microbial dysbiosis and its metabolites play a significant role in MS onset and progression, providing a theoretical basis for identifying therapeutic targets and gut\u2013CNS axis interventions. Experimental validation is needed to confirm mechanisms and translational potential.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/mi\/3572399","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T08:02:31Z","timestamp":1770710551000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gut Microbiota\u2010Derived Metabolites Regulate CASP3 and Neuroimmune Pathways in Multiple Sclerosis: An Integrative Multiomics Study"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9809-2619","authenticated-orcid":false,"family":"Li 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