Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis

Yong guo Zhang, Shaoping Wu, Jianxun Yi, Yinglin Xia, Dapeng Jin, Jingsong Zhou, Jun Sun

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Abstract

Purpose Emerging evidence has demonstrated that gut microbiome plays essential roles in the pathogenesis of human diseases in distal organs. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Treatment with the only drug approved by the US Food and Drug Administration for use in ALS, riluzole, extends a patient׳s life span by only a few months. Thus, there is an urgent need to develop novel interventions that for alleviate disease progression and improve quality of life in patients with ALS. Here we present evidence that intestinal dysfunction and dysbiosis may actively contribute to ALS pathophysiology. Methods We used G93A transgenic mice as a model of human ALS. The G93A mice show abnormal intestinal microbiome and damaged tight junctions before ALS disease onset. The mice were given 2% butyrate, a natural bacterial product, in the drinking water. Results In mice fed with butyrate, intestinal microbial homeostasis was restored, gut integrity was improved, and life span was prolonged compared with those in control mice. At the cellular level, abnormal Paneth cells—specialized intestinal epithelial cells that regulate the host–bacterial interactions—were significantly decreased in the ALS mice treated with butyrate. In both ALS mice and intestinal epithelial cells cultured from humans, butyrate treatment was associated with decreased aggregation of the G93A superoxide dismutase 1 mutated protein. Implications The findings from this study highlight the complex role of the gut microbiome and intestinal epithelium in the progression of ALS and present butyrate as a potential therapeutic reagent for restoring ALS-related dysbiosis.

Original languageEnglish (US)
Pages (from-to)322-336
Number of pages15
JournalClinical Therapeutics
Volume39
Issue number2
DOIs
StatePublished - Feb 1 2017

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Keywords

  • ALS
  • butyrate
  • dysbiosis
  • intestinal permeability
  • microbiome
  • tight junctions

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