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An innovative study by Israeli researchers suggests that intestinal microbes could have a direct effect on the development of amyotrophic lateral sclerosis (ALS), the incurable and fatal neurodegenerative disease, also known as Lou Gehrig's disease. , which affected the physicist Stephen Hawking.
Published today in Nature, a study by researchers at the Weizmann Institute found that the progression of a disease similar to ALS in laboratory mice was slowed down after some mice had received certain strains of intestinal microbes or substances secreted by these microbes.
Weizmann's study has been increasingly revealing the effect of the gut microbiome on brain function and disease. Further research is needed to determine if gut microbiome regulation could have the same effect in humans with ALS as in mice.
"Our long-standing scientific and medical goal is to elucidate the impact of the microbiome on human health and disease, with the brain constituting a fascinating new frontier," said Professor Eran Elinav of the US Department of Health. immunology of Weizmann.
Scientists from Elinav's laboratory, working with colleagues from Professor Eran Segal of the Department of Computer Science and Applied Mathematics, first demonstrated that the symptoms of a disease resembling the ALS in modified mice became worse after the administration of antibiotics to these mice. substantial part of their microbiome.
In addition, scientists found that mice prone to ALS had difficulty surviving when they were grown under conditions free of germs and that they could not develop any intestinal microbiome at all.
Using advanced computation methods, scientists identified 11 microbial strains that were altered in mice prone to ALS during the course of the disease or even before mice developed obvious symptoms.
The scientists isolated these microbial strains and pbaded them one by one to mice prone to ALS, following an antibiotic treatment to eliminate their microbiome. Akkermansia muciniphila, a particular strain, significantly slowed the progression of the disease in mice and prolonged their survival.
To reveal the mechanism by which Akkermansia could produce its effects, scientists examined thousands of small molecules secreted by intestinal microbes. They discovered a molecule called nicotinamide (NAM) and found that its concentrations in the blood and in the cerebrospinal fluid of ALS-prone mice were reduced after antibiotic treatment and increased after the addition of Akkermansia to these mice, which can secrete nicotinamide.
To confirm that nicotinamide was a molecule secreted by a microbiome that could hinder the evolution of ALS, scientists continually infused nicotinamide into ALS-prone mice. The clinical status of these mice has improved significantly. Studies on the brain have shown that the substance appears to have improved the functioning of their motor neurons.
What is the link with human patients with ALS?
Then comes a step that seems most promising for human patients with ALS.
The researchers examined the microbiome and metabolite profiles of 37 people with ALS and compared them to those of members of the same family.
They not only found that the intestinal microbiomes of ALS patients were distinct from those of the family in terms of composition and functional characteristics, but they also found that the microbial genes involved in nicotinamide synthesis were significantly suppressed in ALS patients. .
An badysis of thousands of small molecules in the blood also revealed a distinct pattern in ALS patients compared to controls. Here too, many intermediate molecules involved in the synthesis of nicotinamide have been modified in the blood of ALS patients.
The researchers also found that the nicotinamide levels themselves were significantly reduced in the blood and brain of 60 human ALS patients compared to controls. In addition, there was a correlation between reduced levels of nicotinamide and the degree of muscle weakness in patients.
"These findings are only a first step towards a comprehensive understanding of the potential impact of the microbiome on ALS," said Elinav, "but they suggest that in the future, various ways to modify the microbiome could be used to develop new therapeutic options. for ALS. "
The study was led by postdoctoral fellows Eran Blacher and Stavros Bashiardes, as well as senior scientist Hagit Shapiro from Elinav's laboratory. They collaborated with Daphna Rothschild, a postdoctoral researcher from the Segal laboratory, and Dr. Marc Gotkine, director of the motor neuron diseases clinic at the Hadbadah-Hebrew Medical Center, as well as other scientists from Weizmann, Hebrew University, Ben-Gurion University of Negev, University of Gothenburg, Sweden.
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