A recent study led by Dr. Jun Sun (Department of Medicine, University of Illinois, Chicago, USA) has found that butyrate, a bacterial metabolic by-product, may normalize the intestinal environment, including gut microbiota composition, and increase life span in a mouse model of amyotrophic lateral sclerosis (ALS). In humans, ALS (also known as Lou Gehrig’s disease) is a neurodegenerative disease in which upper and lower motor neurons progressively degenerate.
Jun Sun, leading author of the study, corresponded with GMFH editors about the significance of the work.
Current research has started looking to the gut as a new target for ALS treatment. What is your previous experience regarding the role of intestinal homeostasis (especially intestinal epithelium structure and permeability), the gut microbiome and inflammatory state in the progression of ALS?
While ALS is primarily recognized as a neuromuscular disease, the evidence of gastrointestinal (GI) defects in the pathology of ALS is limited. Our lab working along with collaborator Dr. Jingsong Zhou has made important findings that link intestinal dysfunction to the progression of ALS. For the first time, we identified the leaky intestine [and] imbalanced gut microbiome (dysbiosis) in G93A mice. We have demonstrated changes of gut microbial profile, the level of inflammatory cytokine IL-17, …intestinal junction structure, and intestinal function (permeability and Paneth cells) in an ALS mouse model. Paneth cells are specialized intestinal epithelial cells that regulate the host-bacterial interactions in gut. The abnormal Paneth cells were significantly increased in the G93A mice. Indeed, inflammation in ALS was reported in human ALS. Our data on enhanced IL-17 in blood are in line with the report.
Which is the relationship between ALS and both gut microbiota composition and function?
[ALS] is associated with change[s] of gut microbiota composition and function (e.g. butyrate-producing bacteria). The laboratory mice we used are called ALS mouse model SOD1G93A. Using molecular biology and microbiology methods, we [found] that leaky gut and dysbiosis occur in young G93A mice before the onset of ALS neuromuscular symptoms, suggesting that gut defects may play a role in ALS progression. We found that G93A mice contained reduced level[s] of bacteria that produce butyrate in the intestine. Exactly how ALS-associated mutations in SOD1 affect the gut function and how gut defects contribute to ALS progression became a fundamental question that needs to be addressed.
What does your newest study add?
Our newest study added the potential treatment of ALS by targeting the gut microbiome and intestinal functions. Butyrate is a natural nutrient and bacterial product originating from intestinal fermentation of dietary fibers in the colon, with important roles in physiology of many organs. Treatment of G93A mice with butyrate in drinking water delayed onset of ALS symptoms and prolonged life span. We found that butyrate restored some of the intestinal defects and corrected dysbiosis in the [mouse model of ALS]. At the cellular level, butyrate treatment decreased abnormal Paneth cells. Butyrate reduced aggregation of the G93A-SOD1 mutated protein in both [the ALS mouse model] and cultured human intestinal epithelial cells.
Based on your study, do you think that gut microbiome-targeted treatments may help in slowing disease progression and improving quality of life in patients with ALS?
I see the possibility there. [Converging] evidence has shown that altered intestinal homeostasis and microbiome contribute to the pathology in various [neurodegenerative] diseases. However, we still lack knowledge on the basic biology of GI and microbiome in ALS patients. Our studies have provided the first insight into the potential contribution of the aberrant intestinal homeostasis in ALS progression. I think that gut microbiome-targeted treatments may help in slowing disease progression and improving quality of life in patients with ALS. ALS patients often come to the clinic only after their disease has become symptomatic, making it difficult to understand the early events leading to disease. Our study also suggests the potential to use the intestinal and microbial markers for the diagnosis of ALS.
What further steps is your research group planning to take in the way of targeting the gut microbiota for ALS treatment?
Our study has brought a new concept that gut microbiome may constitute part of the pathophysiology in ALS. We will study the gut-brain axis and human microbiome in ALS.