Gut microbiome influences ALS outcomes

Scientists identify gut-brain connection in ALS

May 13, 2020

Science Daily/Harvard University

Scientists have identified a new gut-brain connection in the neurodegenerative disease ALS. 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. The 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.

Harvard University scientists have identified a new gut-brain connection in the neurodegenerative disease amyotrophic lateral sclerosis, or ALS. 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.

Published in the journal Nature, the findings provide a potential explanation for why only some individuals carrying the mutation develop ALS. They also 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," said Kevin Eggan, 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."

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, 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."

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.

Gut-brain connection

By investigating the connection between genetic and environmental factors in ALS, the researchers identified an important gut-brain connection. The gut microbiome could influence the severity of disease -- whether individuals with the genetic mutation develop ALS, the releated 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."

https://www.sciencedaily.com/releases/2020/05/200513111432.htm

Gut-brain connection helps explain how overeating leads to obesity

August 12, 2019

Science Daily/Baylor College of Medicine

A multi-institutional team reveals a previously unknown gut-brain connection that helps explain how those extra servings lead to weight gain.

Eating extra servings typically shows up on the scale later, but how this happens has not been clear. A new study published today in the Journal of Clinical Investigation by a multi-institutional team led by researchers at Baylor College of Medicine reveals a previously unknown gut-brain connection that helps explain how those extra servings lead to weight gain.

Mice consuming a high-fat diet show increased levels of gastric inhibitory polypeptide (GIP), a hormone produced in the gut that is involved in managing the body's energy balance. The study reports that the excess GIP travels through the blood to the brain where it inhibits the action of leptin, the satiety hormone; consequently, the animals continue eating and gain weight. Blocking the interaction of GIP with the brain restores leptin's ability to inhibit appetite and results in weight loss in mice.

"We have uncovered a new piece of the complex puzzle of how the body manages energy balance and affects weight," said corresponding author Dr. Makoto Fukuda, assistant professor of pediatrics at Baylor and the USDA/ARS Children's Nutrition Research Center at Baylor and Texas Children's Hospital.

Researchers know that leptin, a hormone produced by fat cells, is important in the control of body weight both in humans and mice. Leptin works by triggering in the brain the sensation of feeling full when we have eaten enough, and we stop eating. However, in obesity resulting from consuming a high-fat diet or overeating, the body stops responding to leptin signals -- it does not feel full, and eating continues, leading to weight gain.

"We didn't know how a high-fat diet or overeating leads to leptin resistance," Fukuda said. "My colleagues and I started looking for what causes leptin resistance in the brain when we eat fatty foods. Using cultured brain slices in petri dishes we screened blood circulating factors for their ability to stop leptin actions. After several years of efforts, we discovered a connection between the gut hormone GIP and leptin."

GIP is one of the incretin hormones produced in the gut in response to eating and known for their ability to influence the body's energy management. To determine whether GIP was involved in leptin resistance, Fukuda and his colleagues first confirmed that the GIP receptor, the molecule on cells that binds to GIP and mediates its effects, is expressed in the brain.

Then the researchers evaluated the effect blocking the GIP receptor would have on obesity by infusing directly into the brain a monoclonal antibody developed by Dr. Peter Ravn at AstraZeneca that effectively prevents the GIP-GIP receptor interaction. This significantly reduced the body weight of high-fat-diet-fed obese mice.

"The animals ate less and also reduced their fat mass and blood glucose levels," Fukuda said. "In contrast, normal chow-fed lean mice treated with the monoclonal antibody that blocks GIP-GIP receptor interaction neither reduced their food intake nor lost body weight or fat mass, indicating that the effects are specific to diet-induced obesity."

Further experiments showed that if the animals were genetically engineered to be leptin deficient, then the treatment with the specific monoclonal antibody did not reduce appetite and weight in obese mice, indicating that GIP in the brain acts through leptin signaling. In addition, the researchers identified intracellular mechanisms involved in GIP-mediated modulation of leptin activity.

"In summary, when eating a balanced diet, GIP levels do not increase and leptin works as expected, triggering in the brain the feeling of being full when the animal has eaten enough and the mice stop eating," Fukuda said. "But, when the animals eat a high-fat diet and become obese, the levels of blood GIP increase. GIP flows into the hypothalamus where it inhibits leptin's action. Consequently, the animals do not feel full, overeat and gain weight. Blocking the interaction of GIP with the hypothalamus of obese mice restores leptin's ability to inhibit appetite and reduces body weight."

These data indicate that GIP and its receptor in the hypothalamus, a brain area that regulates appetite, are necessary and sufficient to elicit leptin resistance. This is a previously unrecognized role of GIP on obesity that plays directly into the brain.

Although more research is needed, the researchers speculate that these findings might one day be translated into weight loss strategies that restore the brain's ability to respond to leptin by inhibiting the anti-leptin effect of GIP.

https://www.sciencedaily.com/releases/2019/08/190812160533.htm