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Israeli Research: Motor neuron disease link to microbes in the gut

The study could lead to new treatments for a neurodegenerative condition such as ALS

Scientists at the Weizmann Institute of Science have found in mice that the intestinal microbes, collectively termed the gut microbiome, may affect the motor neuron disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. A form of the disease that affected the cosmologist Stephen Hawking,

A progression of an ALS-like disease was slowed after the mice received a microbe called Akkermansia muciniphila, produce a molecule called nicotinamide which slows the course of motor neuron disease by improving the function of muscle-controlling neurons in the brain.

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The findings report in Nature, are preliminary. However, Prof. Eran Elinav of the Immunology Department says “Our long-standing scientific and medical goal is to elucidate the impact of the microbiome on human health and disease, with the brain being a fascinating new frontier. Given increasing evidence that microbiome affects brain function and disease, we wanted to
study its potential role in ALS,” he says.

The scientists started out demonstrating in a series of experiments that the symptoms of an ALS-like disease worsened after these mice were given broad-spectrum antibiotics to wipe out a substantial portion of their microbiome.
The scientists found that growing these mice in conditions in which, mice carry no microbiome of their own, is exceedingly difficult, as these mice had a hard time surviving in the sterile environment. These results hinted at a potential link between alterations in the microbiome and accelerated disease progression in mice susceptible to ALS.

Next, using advanced computational methods, the scientists identified 11 microbial strains that became altered in mice as the disease progressed or even before the mice developed overt ALS symptoms.

When the scientists gave mice isolated microbial strains one by one – in the form of probiotic-like supplements –following antibiotic treatment, some of these strains had a clear negative impact on the ALS-like disease. But one strain called , Akkermansia muciniphila, significantly slowed disease progression in the mice and prolonged their survival.

To reveal the mechanism by which Akkermansia may be producing its effect, the scientists examined thousands of small molecules secreted by the gut microbes. They zeroed in on one molecule called nicotinamide (NAM): Its levels in the blood and in the cerebrospinal fluid of ALS-prone mice were reduced following antibiotic treatment and increased after these mice were
supplemented with Akkermansia, which was able to secrete this molecule. To confirm that NAM was indeed a microbiome-secreted molecule that could hinder the course of ALS, the scientists continuously infused the ALS-prone mice with NAM. The clinical condition of these mice improved significantly. A detailed study of gene expression in their brains suggested that NAM
improved the functioning of their motor neurons.

Finally, the researchers examined the microbiome and metabolite profiles of 37 human ALS patients and compared them to those of family members sharing the same household. A detailed genomic analysis suggested that the gut microbiomes of ALS patients were distinct in composition and functional features from those of healthy controls. In particular, numerous microbial genes involved in the synthesis of NAM were significantly suppressed in ALS patients. An analysis of thousands of small molecules in the blood also revealed a distinct pattern in ALS patients as compared to controls. Here too, many of the intermediary molecules involved in the NAM synthesis were altered in the blood of ALS patients. When the researchers tested the levels of NAM itself, they found these to be significantly reduced in both the blood and the brain of 60 human ALS patients as compared to controls. Moreover, there was a correlation between reduced NAM levels and the degree of muscle weakness in the patients.

“These findings are only a first step towards achieving a comprehensive understanding of the potential impact of the microbiome on ALS,” Elinav says, “but they suggest that in the future, various means of altering the microbiome may be harnessed for developing new therapeutic options for ALS.”



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