{"doi":"10.1002/cph4.70009","title":"Synergistic Effects of Riluzole and Sodium Butyrate on Barrier Function and Disease Progression of Amyotrophic Lateral Sclerosis Through the Gut‐Neuron Axis","abstract":"ABSTRACT Emerging evidence has shown that gut‐brain barrier dysfunction occurs at the early stages of ALS. Previous studies demonstrated that sodium butyrate significantly prolonged the life span of ALS mice. Riluzole is the first FDA‐approved drug for ALS treatment. We hypothesize that Riluzole and sodium butyrate combined treatment further decreases aggregation of the h‐SOD1 G93A , restores the gut‐brain barrier function, and delays ALS progression. SOD1 G93A mice (9–10‐week‐old) were treated with Riluzole (10 mg/kg, I.P. daily), sodium butyrate (2% in drinking water), or Riluzole and sodium butyrate combination for 6 weeks. The Riluzole/butyrate combination showed a significantly longer rotarod time, increased grip strength, and enhanced intestinal barrier, as compared with Riluzole or sodium butyrate‐only treatment. More reduction of h‐SOD1 G93A aggregation was observed in the colon, spinal cord lumbar, and brain cortex with Riluzole and sodium butyrate combination, compared with Riluzole or sodium butyrate‐only treatment. Tight junction proteins (ZO‐1 and Claudin‐5) 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‐SOD1 G93A aggregation, and inflammatory cytokines more than those in Riluzole or sodium butyrate‐only treatment. Overall, Riluzole and sodium butyrate treatment is more effective than either Riluzole or sodium butyrate‐only in delaying ALS progress. It provides a potential therapeutic strategy and mechanism by restoring barrier function through the gut‐brain axis for ALS.","journal":"Comprehensive physiology","year":2025,"id":518169,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1385594,"name":"KaReisha Robinson","orcid":null,"position":1,"is_corresponding":false},{"id":348078,"name":"Yinglin Xia","orcid":"0000-0001-6857-7437","position":2,"is_corresponding":false},{"id":255752,"name":"Jun Sun","orcid":"0000-0001-7465-3133","position":3,"is_corresponding":false},{"id":348076,"name":"Yongguo Zhang","orcid":"0000-0002-8299-0233","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:49:04.756302Z","pmid":"40176466","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}