Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis

Abstract

Purpose Emerging evidence has demonstrated that gut microbiome plays essential roles in the pathogenesis of human diseases in distant organs. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Treatment with the only FDA approved drug, Riluzole, extends patient life span only for a few months. Thus, there is an urgent need to develop novel interventions for alleviating the disease progression and improving the quality of life for ALS patients. 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, which occur before ALS disease onset. Feeding of the G93A mice with butyrate, a natural bacterial product. Results Feeding of the G93A mice with butyrate, restores the intestinal microbial homeostasis, improves the gut integrity, and prolongs the life span of the ALS mice. Paneth cells are specialized intestinal epithelial cells that regulate the host-bacterial interactions. At the cellular level, we show that abnormal Paneth cells were significantly decreased in the ALS mice treated by butyrate. Butyrate treatment decreases aggregation of the G93A-SOD1 mutated protein in both ALS mice and cultured human intestinal epithelial cells. Implications Our study highlights the complex role of gut microbiome and intestinal epithelium in the progression of ALS and presents butyrate as a potential therapeutic reagent to restore ALS dysbiosis.

Gut inflammation and dysbiosis in human motor neuron disease

“…To the best of our knowledge this is the first comprehensive examination of The Physiological Society and the American Physiological Society inflammatory markers in the stool of patients with motor neuron disease. An aberrant microbiome has been reported in prior studies of humans and in the SOD1 G93A mouse model in which dysbiosis and a loss of intestinal homeostasis are associated with disease progression (Fang et al 2016;Zhang et al 2017). Our current findings add to this line of investigation suggesting a potential role for gut inflammation and microbiome in the development and/or progression of human ALS and MND.…”

“…; Zhang et al. ). Our current findings add to this line of investigation suggesting a potential role for gut inflammation and microbiome in the development and/or progression of human ALS and MND.…”

“…Along these lines, treatment with butyrate delays disease onset in the SOD1 G93A mouse (Zhang et al. ). In ALS patients, patient 4 had low butyrate and total SCFA levels in the stool samples and patient 5 had borderline Low of total SCFAs.…”

“…SOD1 G93A mice harbor the human Cu/Zn superoxide dismutase gene mutation SOD1 G93A recapitulating the neuronal and muscle impairment of human ALS. We have shown that using the bacterial product butyrate, a short chain fatty acid (SCFA), improves gut integrity and microbial homeostasis and prolongs lifespan of SOD1 G93A mice (Zhang et al 2017). In this study, we comprehensively examined the gut microbiome and evaluated markers of intestinal inflammation in five patients with MND.…”

Energy metabolism in amyotrophic lateral sclerosis: assessment of body composition and energy expenditure

“…Furthermore, correction of the gut microbiome with butyrate in this model has been shown to restore gut integrity and prolong survival (Zhang et al, 2017). While gut microbes have not been studied in ALS patients, it is plausible that the dietary changes that occur in ALS (Slowie et al, 1983, Kasarskis et al, 1996 could contribute to adaptations in the gut microbiome.…”