Pioneering research reveals certain human genes relate to gut bacteria

June 22, 2020

Science Daily/University of Bristol

The role genetics and gut bacteria play in human health has long been a fruitful source of scientific inquiry, but new research marks a significant step forward in unraveling this complex relationship. Its findings could transform our understanding and treatment of all manner of common diseases, including obesity, irritable bowel syndrome, and Alzheimer's disease.

The international study, led by the University of Bristol and published today in Nature Microbiology, found specific changes in DNA -- the chains of molecules comprising our genetic make-up -- affected both the existence and amount of particular bacteria in the gut.

Lead author Dr David Hughes, Senior Research Associate in Applied Genetic Epidemiology, said: "Our findings represent a significant breakthrough in understanding how genetic variation affects gut bacteria. Moreover, it marks major progress in our ability to know whether changes in our gut bacteria actually cause, or are a consequence of, human disease."

The human body comprises various unique ecosystems, each of which is populated by a vast and diverse array of microorganisms. They include millions of bacteria in the gut, known as the microbiome, that help digest food and produce molecules essential for life, which we cannot produce ourselves. This has prompted researchers to question if gut bacteria may also directly influence human health and disease.

Previous research has identified numerous genetic changes apparently related to bacterial composition in the gut, but only one such association has been observed consistently. This example involves a well-known single mutation that changes whether someone can digest the sugar (lactose) in fresh milk. The same genetic variation also predicts the prevalence of bacteria, Bifidobacterium, that uses or digests lactose as an energy source.

This study, the biggest of its kind, identified 13 DNA changes related to changes in the presence or quantity of gut bacteria. Researchers at Bristol worked with Katholieke Universiteit Leuven and Christian-Albrecht University of Kiel to analyse data from 3,890 individuals from three different population studies: one in Belgium (the Flemish Gut Flora Project) and two in Germany (Food Chain Plus and PopGen). In each individual, the researchers measured millions of known DNA changes and, by sampling their feces, also registered the presence and abundance of hundreds of gut bacteria.

Dr Hughes said: "It was exciting to identify new and robust signals across the three study populations, which makes the correlation of genetic variation and gut bacteria much more striking and compelling. Now comes the great challenge of confirming our observations with other studies and dissecting how exactly these DNA changes might impact bacterial composition."

Such investigations could hold the key to unlocking the intricate biological mechanisms behind some of the biggest health challenges of our time.

Study co-author Dr Kaitlin Wade, Lecturer in Epidemiology at the University of Bristol, said: "A strength here is that these findings provide a groundwork for causal analyses to determine, for instance, whether the presence of specific bacteria increases the risk of a disease or is a manifestation of it."

"The implications for our understanding of human health and our approach to medicine are far-reaching and potentially game changing."

https://www.sciencedaily.com/releases/2020/06/200622133018.htm

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

Transplanting gut bacteria alters depression-related behavior, brain inflammation in animals

Knowledge of stress biology may eventually yield bacterial treatments for psychiatric disorders

May 6, 2019

Science Daily/Children's Hospital of Philadelphia

Scientists have shown that transplanting gut bacteria, from an animal that is vulnerable to social stress to a non-stressed animal, can cause vulnerable behavior in the recipient. The research reveals details of biological interactions between the brain and gut that may someday lead to probiotic treatments for human psychiatric disorders such as depression.

"In rats that show depressive-type behavior in a laboratory test, we found that stress changes their gut microbiome -- the population of bacteria in the gut," said study leader Seema Bhatnagar, PhD, a neuroscientist in Department of Anesthesiology and Critical Care at Children's Hospital of Philadelphia (CHOP). "Moreover, when we transplanted bacteria from those stress-vulnerable rats into rats that had not been stressed, the recipient animals showed similar behavior."

Bhatnagar added that stress also increased inflammation in the brains of vulnerable rats, and that this inflammation appeared in unstressed rats after they received transplants from vulnerable animals.

The study team published its findings online March 4, 2019 in Molecular Psychiatry.

Bhatnagar leads the Stress Neurobiology Program at CHOP, and many of her co-authors are members of the PennCHOP Microbiome Program, a collaboration between researchers at CHOP and the Perelman School of Medicine at the University of Pennsylvania. The program aims to better understand the communities of microbes inside our bodies and alter their properties to improve human health. Chunyu Zhao, PhD, of that program, performed microbiome data analysis and is a co-author of the paper.

Scientists already know that brain and gut influence each other. In humans, patients with psychiatric disorders have different populations of gut microbes compared to microbes in healthy individuals, with parallel findings also seen in animal models of psychiatric disease. This study investigated mechanisms related to brain inflammation, microbiomes and stress.

"Humans do not all react identically to the same stresses -- some are more vulnerable than others to developing psychiatric disorders, others are more resilient," said Bhatnagar. "Something similar happens in laboratory animals as well."

In rodents, social hierarchies and territoriality are major sources of stress. In the laboratory, researchers model stressors with validated behavioral tools such as a forced swim test or a social defeat test to examine how animals use coping strategies to deal with stress. Rats that cope more passively are more vulnerable to the effects of stress because they also exhibit more anxiety- and depressive-type behaviors, while rats that cope more actively are resilient to the effects of social stress. Based on these assessments, the researchers classified the animals as either vulnerable or resilient.

The study team then analyzed the fecal microbiomes of vulnerable rats, resilient rats, a non-stressed control group, and a placebo group. They found that vulnerable rats had higher proportions of certain bacteria, such as Clostridia, than the other groups.

They then performed fecal transplants from three donor groups -- vulnerable rats, resilient rats or control non-stressed rats -- into naïve rats, animals that had not been stressed. They found that different microbiomes changed depressive-like behavior. Rats receiving transplants from vulnerable rats were more likely to adopt depressive-like behaviors, whereas rats receiving transplants from resilient animals or non-stressed animals did not exhibit any changes in behavior or in neural measures. Patterns of brain inflammatory processes in recipients also resembled those seen in the brains of vulnerable animals, suggesting that immune-modulating effects of gut bacteria such as Clostridia may have promoted that inflammation. However, transplants did not significantly change anxiety-like behavior.

The finding that gut transplants from vulnerable rats increased depressive-type behavior but not anxiety-type behavior in non-stressed recipients may point to different mechanisms. The authors said this difference suggests that depressive-type behaviors are more regulated by the gut microbiome, whereas anxiety-type behaviors are primarily influenced by neural activity changes produced by stress experience.

"Although much more research remains to be done, we can envision future applications in which we could leverage knowledge of microbiome-brain interactions to treat human psychiatric disorders," said Bhatnagar. "People already are taking over-the-counter probiotics as supplements. If we can eventually validate beneficial behavioral effects from specific bacteria, we could set the stage for new psychiatric treatments."

https://www.sciencedaily.com/releases/2019/05/190506163642.htm