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A metabolite from gut microbes seems to make ALS less severe in mice

Nicotinamide may play a protective role in the progression of the neurodegenerative disease

by Megha Satyanarayana
July 23, 2019 | A version of this story appeared in Volume 97, Issue 30


A micrograph of <i>Akkermansia muciniphila </i>.
Credit: Willem de Vos/University of Helsinki/Wageningen Univ.
Akkermansia muciniphila and a metabolite that it produces, nicotinamide, may play a protective role in amyotrophic lateral sclerosis.

A chemical released by bacteria in the intestines may play a protective role in the progression of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), according to a new study (Nature 2019, DOI: 10.1038/s41586-019-1443-5). These findings are the latest in a stream of research linking brain health to gut microbes.

Eran Elinav, the Weizmann Institute of Science researcher who led the study, says that these results support the idea that ALS, which is commonly known as Lou Gehrig’s disease, could be influenced by the environment as much as through genetics. “We thought it would be interesting and potentially important to see whether such environmental factors could possibly impact the course or severity of ALS through effects mediated by the microbiome,” he says.

To investigate the role of the microbiome in ALS, Elinav’s group studied mice that are engineered to carry a genetic change that leads to ALS in humans. The researchers first treated these ALS mice with antibiotics, to deplete their gut microbes. In standard tests of motor function, the mice performed poorly compared with mice not given antibiotics, suggesting that the composition of gut microbes might have an effect on disease progression.

When comparing the species of bacteria in the guts of mice with ALS versus their healthy brothers and sisters, the team noted that several species were more abundant in one group compared with the other. One by one, the scientists transplanted those species, including Akkermansia muciniphila and multiple Parabacteroides and Lactobacillus species, into mice without any gut microbes, and found that two species made ALS symptoms worse—Ruminococcus torques and Parabacteroides distasonis. Meanwhile, A. muciniphila made symptoms better.

The scientists also found that ALS mice given A. muciniphila had higher levels of a bacterial metabolite called nicotinamide compared with those that didn’t get the microbial species. Giving the ALS mice direct injections of nicotinamide improved the animals’ motor function.

Nicotinamide, which is a form of vitamin B-3 and part of metabolic pathways that produce energy in a cell, has previously been shown to have a role in the health of neurons and the central nervous system (Int. J. Tryptophan 2018, DOI: 10.1177/1178646918776658). Elinav says he’s not sure what nicotinamide is doing in their model of ALS, but it may be involved in reducing oxidative stress in the nervous system.

The team then looked for a nicotinamide-ALS connection in humans. In early studies in 37 people with ALS, Elinav’s group observed that the gut microbiomes of people with ALS were different compared with the people who lived with them. Also people with ALS had less nicotinamide in their cerebrospinal fluid compared with their housemates. While it was hard to tell a difference in amounts of A. muciniphila between the two groups, people with ALS had a smaller number of microbial genes involved in nicotinamide synthesis in their feces, and many of these genes appeared to come from A. muciniphila, suggesting those with ALS may have less of that species in their guts.

a structure of superoxide dismutase 1
Credit: Wikipedia
Mutations in the gene encoding the enzyme superoxide dismutase 1 can lead to ALS in people.

Elinav says their next steps are to test larger groups of people with ALS in different locations, as microbial signatures vary from place to place and from person to person. He wants to see if they can come up with a microbial signature that defines people with ALS. He also points out that it’s too early to say that treating people with ALS with either nicotinamide or fecal transplants containing A. muciniphila would alleviate disease symptoms.

Brett Finlay, a microbiome expert at the University of British Columbia, says that Akkermansia is a hot topic for those studying the gut microbiome. In some studies, the species has a beneficial effect, and in others, it does not. He says Elinav’s work points to a role of the microbiome in ALS progression, and that while nicotinamide may be a driver, it may not be the only bacterial metabolite involved as bacteria often work in communities.

“This is one of those papers that opens up a whole bunch of avenues of research that we weren’t thinking about a week ago,” Finlay says.


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