New Phase of Microbiome Research

Interrogating the microbiome to find answers about disease

colorful digital illustration of bacteria in the gut

Image: ChrisChrisW/iStock/Getty Images Plus

Trillions of microbes—bacteria, viruses, fungi—colonize in our bodies, and their genome of genetic instructions work alongside ours.

Over the past two decades of microbiome research, scientists have accumulated a veritable field guide to these microbes that live on, in and around us, and they have begun to understand the integral role microbes play in our digestion and immune system, as well as their contribution to health and disease.

“I think microbiome research is entering an exciting new phase where we can start tying things together to get a firmer grasp on the mechanisms of what’s happening to microbes in humans over time and how it relates to disease,” said Georg Gerber, Harvard Medical School associate professor of pathology and chief of the Division of Computational Pathology at Brigham and Women’s Hospital.

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Gerber has focused the past decade on creating computational biology and machine learning methods and applying them to better understand the role these microbes play in health and illness, with the idea of intervening to correct microbiota imbalances which have been linked to a growing array of disorders, including obesity, diabetes and cancer.

Gerber has devised new computational models and methods to investigate how the lack or presence of certain bacteria could lead to food allergies and to predict the recurrence of C. difficile infection in patients.

On a recent project, he and co-principal investigator Harris Wang of Columbia University created new technologies to decipher rules that govern the colonization and maintenance of these extremely complex microbial communities over time.

They are drilling down to the microbes’ genetic level with the latest in synthetic biology technologies created by Wang. They are also stepping back to capture a more holistic picture of how microbes are behaving over time, and in what locations, by applying the computational tools Gerber has devised to find meaning from massive amounts of data.

Collaboration key

“For this next research phase to be successful, it is going to require these kinds of collaborations that span the computational piece with the creative high-throughput way of looking at biological problems that Harris does,” Gerber commented. He has collaborated in the past with Wang, who used to work in George Church’s lab at HMS.

Gerber and Wang are using a mouse model to see what happens when new microbes are added to a mouse’s existing microbiota—looking at which microbes colonize, which are excluded, and why colonization or exclusion occurs. They are also observing what happens to the microbe mix when mice, caged separately and each with its own unique combination of microbes, are put together with others in the same cage.

“This is like, if we travel to a different place, or even interact with other people locally,” he explained. “We are exchanging microbiomes.”

Each of us hosts our own unique combination of microbes, adding to the microbiome complexity, but this increases the potential for personalized microbiome-based therapies.

With the experimental technologies they are devising, Gerber also hopes to determine if the microbes’ location in the gut makes a difference. For example, is there a difference in microbes located close to epithelial cells, which are integral to crosstalk between the microbes and the host’s immune system?

“If we can make progress in understanding these mechanisms and roles, I think it can give us real insights into therapeutics that will work for a number of infectious diseases, autoimmune diseases like rheumatoid arthritis, and other microbiome-related diseases,” he said.

Gerber, along with Lynn Bry, HMS associate professor of pathology and director of Massachusetts Host-Microbiome Center at Brigham and Women’s, and Talal Chatila, the HMS Denise and David Bunning Professor of Pediatrics in the Field of Allergy and Immunology at Boston Children’s Hospital, have used their findings to develop a cocktail of bacteria to try to restore microbial balances and develop a potential cure for food allergies.

Tools to interrogate

Gerber believes that it is critical to mechanistically understand and then predict what happens when scientists do interventions.

“It’s a very complicated system, so you can’t just observe what happens empirically,” he said. “Targeting one part of the system may have cascading effects throughout the whole system. To benefit health, you have to be able to understand the rules and mechanisms.”

Gerber’s lab has created a new tool, MDSINE2, to predict the behavior and dynamics of hundreds of microbes at one time, a significant increase over what current technologies can do, he said. For another project, the team developed an algorithm called MITRE, which allows them to observe the microbiome over time, and predict, for example, if someone is going to get food allergies or not.

These technologies not only have implications for human health, but they may also help scientists understand other microbial ecosystems. In the future, samples from soil or water reservoirs could be “interrogated” using Wang’s molecular methods and Gerber’s computational tools.

This could even yield clues to understanding bacteria like E. coli that don’t just remain in the human gut but circulate through the environment, humans and other animals.

In addition to computational research devoted to technology development, Gerber’s lab has many active projects underway that have clinical applications. He has a number of projects related to C. difficile infection, in collaboration with Bry, whom he said brings a deep understanding of microbial and host microbiology, and Jessica Allegretti, HMS assistant professor of medicine, a gastroenterologist and director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital.

Gerber and Bry met 10 years ago when he was a resident on his microbiology rotation at Brigham and Women’s, and she inspired him to focus on microbiome research.

Funding new ideas

Supported by Harvard Catalyst microbiome pilot funding over the past year through the Translational Innovator program, Gerber, Bry and Allegretti have been investigating whether a microbiome-focused clinical test can predict whose C. difficile infections will recur, which happens about 25 percent of the time. If identified, affected individuals can be given further treatment before infection sets in.

The researchers looked first at the microbiome using genetic sequencing and found they couldn’t make reliable predictions on that basis.

“But when we looked at the metabolites in the gut, both the substances produced by the host as well as microbial metabolites, we found we can predict pretty well whose infections will recur,” he said.

Larger studies need to verify the preliminary findings, and then human trials can begin.

Gerber credits Harvard Catalyst for providing pilot grants that have helped him get ideas off the ground, accelerating progress. Last year, he received a Brigham and Women’s President’s Scholar award, which comes with unrestricted funding, giving him the freedom to work on new projects of his choice.

“These kinds of programs are invaluable because they take a risk and fund ideas at earlier stages, or in new directions that wouldn’t be funded elsewhere,” he said.

Gerber is confident that with his collaborators he has the right mix of expertise for the challenges ahead.

“I’m super excited that we can begin to tie all the pieces together to make truly useful clinical predictions and interventions,” he said.

Gerber’s research has been supported by grants from the National Institutes of Health, Defense Advanced Research Projects Agency and National Science Foundation.