Changing the composition of bacteria in the gut using antibiotics or fecal transplants may help prevent or reduce the severity of symptoms of amyotrophic lateral sclerosis (ALS), a study in mice with the most common ALS mutation shows.
This gut-brain connection may help explain why some patients with this mutation have less severe symptoms than others, while also providing a starting point to develop therapeutic strategies that target the gut microbiome for treating ALS.
The study, “C9orf72 suppresses systemic and neural inflammation induced by gut bacteria,” was published in Nature.
The collection of microorganisms living in our guts (gut microbiota) is increasingly recognized as a key factor determining susceptibility to conditions such as multiple sclerosis and Parkinson’s disease, and studies are also emerging that link the gut microbiome with ALS.
Research has shown that people with ALS have an abnormal gut microbiota, and mouse models of the disease have suggested that changes in the microorganisms filling the gut can exacerbate neurodegeneration and cause animals to die earlier.
In this study, researchers at Harvard University shed more light on how the gut microbiota can contribute to disease.
The team was studying a mouse model of ALS carrying a mutant version of the C9orf72 gene, resulting in a deficiency in the encoded C9orf72 protein. These mice have an overactive immune system, including excess inflammation in the brain, and exacerbated movement problems, which shortens their lives.
But other reports studying the exact same model showed marked variation in the long-term survival of these animals, suggesting that the environment in which they are kept can affect their lifespan.
To investigate this further, the team at Harvard developed the model in a new facility at Broad Institute in Cambridge, Massachusetts. Despite having the exact same genetic background, the animals at the Broad facility exhibited no motor symptoms and no shortened lifespan. Animals at Broad also had significantly less inflammation than their Harvard counterparts.
“Many of the inflammatory characteristics that we observed consistently and repeatedly in our Harvard facility mice weren’t present in the Broad facility mice. Even more strikingly, the Broad facility mice survived into old age,” Aaron Burberry, lead author of the study, said in a press release.
“These observations sparked our endeavor to understand what about the two different environments could be contributing to these different outcomes,” Burberry said.
After excluding diet, light cycles and other environmental factors, researchers compared the microbial profiles for the animals in the two facilities. They found that a virus called murine norovirus and the bacteria Pasteurella pneumotropica, Tritrichomonas muris, and Helicobacter all were more common at the Harvard facility than at the Broad facility.
The levels of these bacteria all were within the norms for animal facilities, and none of them is considered pathogenic (harmful), as other animals at Harvard have a normal lifespan. But Helicobacter bacteria, for example, have been suggested to stimulate the immune system.
To find out if changes in gut microbiota were responsible for the differences, the team treated the Harvard facility mice with broad-spectrum antibiotics or fecal transplants from animals at the Broad facility. Both these approaches reduced inflammation.
The collection of gut microbes then was examined in animals from both Harvard and Broad, as well as from the Johns Hopkins University in Baltimore, Maryland (where animals had a shorter lifespan), and from The Jackson Laboratory in Maine (where mice had a longer lifespan).
“At this point, we reached out to the broader scientific community, because many different groups have studied the same genetic mouse model and observed different outcomes,” Burberry said. “We collected microbiome samples from different labs and sequenced them. At institutions hundreds of miles apart, very similar gut microbes correlated with the extent of disease in these mice.”
An analysis of fecal samples as a whole was able to readily discriminate samples collected in a pro-survival environment from those coming from a pro-inflammatory environment. Also, mice from Harvard or Johns Hopkins had much less bacteria diversity and showed changes in the relative abundance of 62 of 301 bacteria, compared to mice reared at the Broad Institute or at The Jackson Laboratory.
The team then examined exactly how the bacteria were driving inflammation and disease in animals. They isolated macrophages — a kind of immune cell that works by engulfing pathogens — from the Harvard facility mice and cultured them in the lab with gut bacteria from either Harvard or Broad animals.
They found that cells cultured with bacteria from the Harvard animals produced significantly higher levels of pro-inflammatory molecules, even when very low concentrations of bacteria were used.
Additional experiments also showed that suppressing the gut microbiota in Harvard animals using antibiotics, significantly reduced immune cell infiltration into their nervous system, and lowered the activation of their native brain immune cells (microglia).
“Our results indicate that when C9orf72 function declines, the environment generally—and the gut microbiota specifically—become potent modifiers of whether autoimmunity, neural inflammation, motor deficits and premature mortality occur,” the researchers wrote.
“We made the remarkable discovery that the same mouse model — with identical genetics — had substantially different health outcomes at our different lab facilities,” said Kevin Eggan, PhD, Harvard professor of stem cell and regenerative biology.
“We traced the different outcomes to distinct gut microbial communities in these mice, and now have an intriguing hypothesis for why some individuals carrying this mutation develop ALS while others do not,” Eggan said.
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