Investigating the Gut-Brain Connection

HSCI researchers study how the gut microbiome affects ALS and the aging brain


By studying two disease models at the same time, Harvard Stem Cell Institute scientists discovered a new gut-brain connection in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease associated with aging. Led by HSCI Principal Faculty member Kevin Eggan, Ph.D., the researchers found that in mice with a common ALS genetic mutation, changing the gut microbiome
using antibiotics or fecal transplants could prevent or improve disease symptoms. Their findings provide a potential explanation for why only some individuals carrying the mutation develop ALS, and point to a possible therapeutic approach based on the microbiome.

“Our study focused on the most commonly mutated gene in patients with ALS. We made the remarkable discovery that the same mouse model — with identical genetics — had substantially different health outcomes at our different lab facilities,” Eggan said. “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.”

Different facilities, different outcomes

The researchers initially studied the ALS genetic mutation by developing a mouse model at their Harvard lab facility. The mice had an overactive immune response, including inflammation in the nervous system and the rest of the body, which led to a shortened lifespan.
In order to run more detailed experiments, the researchers also developed the mouse model in their lab facility at the Broad Institute, where Eggan is the director of stem cell biology at the Stanley Center for Psychiatric Research. Unexpectedly, although the mice had the same genetic mutation, their health outcomes were dramatically different.
“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,” said Aaron Burberry, Ph.D., postdoctoral fellow in the Eggan Lab and lead author of the study. “These observations sparked our endeavor to understand what about the two different environments could be contributing to these different outcomes.”
Microscopy image of the spinal cord.
In mice with a common ALS genetic mutation, the spinal cord has high levels of inflammation (red). Credit: Kevin S. Smith and Aaron Burberry

Searching the gut microbiome

Looking for environmental differences between the mice, the researchers honed in on the gut microbiome. By using DNA sequencing to identify gut bacteria, the researchers 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.
“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.”
The researchers then tested ways to change the microbiome and improve outcomes for the Harvard facility mice. By treating the Harvard facility mice with antibiotics or fecal transplants from the Broad facility mice, the researchers successfully decreased inflammation.

Expanding the gut-brain connection

By examining the connection between genetic and environmental factors in ALS, the researchers identified an important gut-brain connection.
The gut microbiome may influence the severity of disease — whether individuals with the genetic
mutation develop ALS, the related condition frontotemporal dementia, or no symptoms at all — and could be a potential target for therapy.
“Our study provides new insights into the mechanisms underlying ALS, including how the most common ALS genetic mutation contributes to neural inflammation,” Eggan said. “The gut-brain axis has been implicated in a range of neurological conditions, including Parkinson’s disease and Alzheimer’s disease. Our results add weight to the importance of this connection.”
Microscopy image of the mouse brain.
Cross-section of a mouse brain, with green representing one of the top genes whose expression changes with aging. Credit: Rubin Lab, Harvard University
Based on these findings, the researchers will further investigate which specific bacteria in the microbiome are involved, and whether they can be found in patients with ALS. Eggan is also teaming up with HSCI Executive Committee member Lee Rubin, Ph.D., who studies the brain during the healthy aging process. 
Rubin has developed tools to track exactly how the brain changes during aging, by looking at whether new neurons and blood vessels are generated, as well as which genes are expressed by each cell type. By applying these approaches in mice with different microbiomes, researchers will be able to understand the gut’s influence on the brain and the nervous system; how it changes over time, especially in conditions of inflammation which increase with age; and how it can be managed through controlling the microbiome.