title: Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Yong-Guo
authors.initials: YG
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Rush University Medical Center, Chicago, Illinois.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Physiology, Kansas City University of Medicine and Bioscience, Kansas City, Missouri.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Yi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Yinglin
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Jin
authors.affiliation: Department of Physiology, Kansas City University of Medicine and Bioscience, Kansas City, Missouri.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois, Chicago, Illinois. Electronic address: junsun7@uic.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D000069196:Gastrointestinal Microbiome; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D011788:Quality of Life; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: ALS; butyrate; dysbiosis; intestinal permeability; microbiome; tight junctions