Gut microbiome influences ALS outcomes

A new gut-brain connection in the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS) has been discovered by scientists at Harvard University. The researchers discovered that changing the gut microbiome using antibiotics or fecal transplants could prevent or improve disease symptoms in mice with a common ALS genetic mutation.

These results published in the journal Nature provide a potential explanation for why only some individuals carrying the mutation develop ALS. This valuable research could lead to a possible therapeutic approach based on the microbiome.

THE GUT MICROBIOME, AN UNEXPECTED INFLUENCE

The ALS genetic mutation was initially researched by developing a mouse model at the researchers Harvard lab facility. The mice had a shortened lifespan due to inflammation in the nervous system and the rest of the body. The researchers also developed the mouse model in their lab facility at the Broad Institute to carry out more detailed experiments. Unexpectedly, although the mice had the same genetic mutation, the inflammatory characteristics observed consistently and repeatedly in the Harvard facility mice weren’t present in the Broad facility mice, which surprisingly survived into old age.

Considering the environmental differences between the mice, the researchers focused on the gut microbiome. DNA sequencing was used by the researchers to identify the gut bacteria. The research team found specific microbes that were present in the Harvard facility mice but absent in the Broad facility mice, even though the lab conditions were standardized between facilities.

Aaron Burberry, the lead author of the study, said “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. 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.”

The researchers decided to test ways of changing the microbiome to improve outcomes for the Harvard facility mice. The researchers successfully decreased inflammation in the Harvard facility mice by treating the mice with antibiotics or fecal transplants from the Broad facility mice.

THE IMPORTANCE OF THE GUT-BRAIN CONNECTION

The researchers identified an important gut-brain connection by connecting genetic and environmental factors in ALS. This research proves how disease severity can be influenced by the gut microbiome. This is true for individuals who express the genetic mutation for ALS or the related condition frontotemporal dementia, or who are asymptomatic. Therapies targeting the microbiome should be explored for future treatment options.

Abstract:

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3,4,5,6,7,8,9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6,7,8,9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.

References:

Burberry, A., Wells, M.F., Limone, F. et al. (2020) C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature. https://doi.org/10.1038/s41586-020-2288-7

Smith, K. (2020) The Harvard Gazette, https://news.harvard.edu/gazette/story/2020/05/harvard-scientists-identify-gut-brain-connection-in-als/