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Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA\u2010approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h\u2010SOD1<jats:sup>G93A<\/jats:sup>, restores the gut\u2010brain barrier function, and delays ALS progression. SOD1<jats:sup>G93A<\/jats:sup> mice (9\u201310\u2010week\u2010old) were treated with Riluzole (10\u2009mg\/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6\u2009weeks. The Riluzole\/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate\u2010only treatment. More reduction of h\u2010SOD1<jats:sup>G93A<\/jats:sup> aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate\u2010only treatment. Tight junction proteins (ZO\u20101 and Claudin\u20105) significantly increased in the colon, spinal cord lumbar, and brain cortex of mice with Riluzole and sodium butyrate treatment. The Riluzole and sodium butyrate combination reduced serum lipopolysaccharides and h\u2010SOD1<jats:sup>G93A<\/jats:sup> aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate\u2010only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate\u2010only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut\u2010brain axis for ALS.<\/jats:p>","DOI":"10.1002\/cph4.70009","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T14:47:41Z","timestamp":1743778061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut\u2010Neuron Axis"],"prefix":"10.1002","volume":"15","author":[{"given":"Yongguo","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KaReisha","family":"Robinson","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and 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