Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease known to kill the neurons controlling the muscles responsible for the movement of limbs and walking, resulting in the complete paralysis of the patient. ALS is classified as familial or sporadic depending on whether there is a family history of the disease, with the general consensus on the causes of this disorder involving an equal balance of genetic and environmental factors. However, even though numerous genetic variants associated with the disease have been identified, it is still unclear which specific environmental factors are involved in the pathology of ALS. Now, a study from researchers at Harvard University identifies a new gut-brain connection based on genetics in ALS. The team states altering the gut microbiome using antibiotics or fecal transplants could prevent or improve disease symptoms in mice possessing the most common genetic mutation associated with ALS. The study is published in the journal Nature.
Previous studies have implicated specific gut bacteria species in the onset of ALS symptoms, with eleven microbial species suggested to play a part in either increasing or decreasing the progression of the disease. However, the ALS mouse models used in past research utilized genetic mutations not widely representative of the ALS genetic variants present in humans; the most common genetic variant involved in ALS is C9ORF72, a mutation also affiliated with frontotemporal dementia. The current study investigates which environmental factors affect patients with ALS carrying the C9ORF72 gene variant.
The current study bred two groups of mice with the widespread C9ORF72 ALS genetic mutation at two separate laboratories, known as Location A and Location B. The mice produced at Location A were shown to have an overactive immune response, including body-wide inflammation which led to a shortened lifespan. The mice with the identical genetic mutation bred at Location B survived into old age without exhibiting many of the inflammatory symptoms observed in the mice born at Location A. The group then investigated potential variables to account for these extremely different health outcomes, with tests suggesting the animal’s microbiota was the main factor.
Results using DNA sequencing identified specific gut bacteria present in mice reared at Location A that were absent in the healthier mice produced at Location B, even though conditions were standardized at both facilities. Data findings show treating the mice born at Location A with antibiotics or fecal transplants from mice reared at Location B successfully decreased inflammation. The lab states investigating the connection between the most abundant genetic variant in ALS and environmental factors identified an important gut-brain connection.
The team surmises their study involving genetically identical mice displaying vastly different health outcomes identifies gut bacteria as the main driver of this discrepancy. For the future, the researchers state they now plan to further investigate the role of the gut microbiota and genetics in brain health.
Source: Harvard University
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