Zhang Yongguo, Robinson KaReisha, Xia Yinglin, Sun Jun
Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA.
Jesse Brown VA Medical Center, Chicago, Illinois, USA.
Compr Physiol. 2025 Apr;15(2):e70009. doi: 10.1002/cph4.70009.
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, restores the gut-brain barrier function, and delays ALS progression. SOD1 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 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 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.
新出现的证据表明，肠脑屏障功能障碍发生在肌萎缩侧索硬化症（ALS）的早期阶段。先前的研究表明，丁酸钠可显著延长ALS小鼠的寿命。利鲁唑是美国食品药品监督管理局（FDA）批准的首个用于治疗ALS的药物。我们假设，利鲁唑和丁酸钠联合治疗可进一步减少人超氧化物歧化酶1（h-SOD1）的聚集，恢复肠脑屏障功能，并延缓ALS的进展。对9至10周龄的SOD1小鼠分别给予利鲁唑（10毫克/千克，腹腔注射，每日一次）、丁酸钠（饮用水中含2%）或利鲁唑与丁酸钠联合治疗，持续6周。与单独使用利鲁唑或丁酸钠治疗相比，利鲁唑/丁酸钠联合治疗显示转棒试验时间显著延长、握力增加且肠道屏障增强。与单独使用利鲁唑或丁酸钠治疗相比，利鲁唑和丁酸钠联合治疗在结肠、脊髓腰段和大脑皮层中观察到h-SOD1聚集的减少更多。紧密连接蛋白（闭合蛋白1和Claudin-5）在接受利鲁唑和丁酸钠治疗的小鼠的结肠、脊髓腰段和大脑皮层中显著增加。与单独使用利鲁唑或丁酸钠治疗相比，利鲁唑和丁酸钠联合治疗降低血清脂多糖、h-SOD1聚集以及炎性细胞因子的效果更显著。总体而言，利鲁唑和丁酸钠联合治疗在延缓ALS进展方面比单独使用利鲁唑或丁酸钠更有效。它通过肠脑轴恢复屏障功能为ALS提供了一种潜在的治疗策略和机制。
