Chasing the Mysteries of the Microbiome

Maayan Levy, PhD, and Christoph Thaiss, PhD

When we hear about gut bacteria, we may think about probiotics and supplements marketed to help with digestion, about how taking antibiotics might affect our intestinal tract, or perhaps about trendy diets that aim to improve gut health.

But two researchers at Penn Medicine think that understanding the microbiome, the entirety of microbial organisms associated with the human body, might be the key to deciphering the fundamental mechanisms that make our bodies work. They think these microbes may work like  a call center switchboard, making connections to help different organs, biological systems, and the brain communicate. Maayan Levy, PhD, and Christoph Thaiss, PhD, both assistant professors of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, argue that the microbiome is instrumental to revealing how signals from the gastrointestinal tract are received by the rest of the body— which may hold the key to understanding inter-organ communication in general.

While the gut sends signals to all parts of the body to initiate various biological processes, the mechanisms underlying this communication— and communication between different organs involved in these processes—is relatively unknown.

“The more we learn about the role the microbiome plays in a wide range of diseases— from cancer to neurodegenerative diseases to inflammatory diseases — the more important it becomes to understand what exactly its role is,” said Thaiss. “And hopefully once we understand how it works, we can use the microbiome to treat these diseases.”

Revealing the Functions of the Microbiome  

Levy and Thaiss met nearly a decade ago while conducting research at the Weizmann Institute of Science in Israel and married soon after. Thaiss had an interest in immunology since he began his undergraduate degrees in Germany and the United States, studying how the immune system differentiates between microorganisms in the body that cause disease, and those that don’t. From there, he quickly realized how important understanding the microbiome was to answering these questions. 

Levy, on the other hand, first studied developmental biology, specifically how embryos develop, before joining the Elinav Lab at the Weizmann Institute to study the microbiome, where Thaiss was also conducting research for his PhD. 

“The more we researched the microbiome during the early years of this growing field, the more we realized how many processes in the body it seemed linked to,” Levy said. 

Early in his career, Thaiss’ research focused on the role of the microbiome in metabolism. He found that the microbiomes of mice experience a 24-hour circadian rhythm, and that microbial oscillations throughout the day are critically required to maintain homeostasis within the body – including body temperature, blood glucose levels, and hydration – despite changes in internal and external conditions.

In another study, Thaiss identified an intestinal microbiome signature in mice who were obese and lost weight that contributes to faster weight regain. This pattern of changing gut microbes may help to explain the phenomenon of “yo-yo dieting” in humans. 

“These initial studies revealed that the microbiome is involved in many metabolic mechanisms and encouraged us to uncover more about what other processes the microbiome influences, and how,” Thaiss said. 

Levy and Thaiss joined the faculty at Penn Medicine after completing their graduate studies in 2018. Here, they continue to investigate the role of the microbiome in various biological processes. 

In his lab, Thaiss focuses on the impact of the microbiome on the brain. He recently identified species of gut-dwelling bacteria that activate nerves in the gut to promote the desire to exercise. Most recently, Thaiss published a study that identified the cells that communicate psychological stress signals from the brain to the gastrointestinal tract, and cause symptoms of inflammatory bowel disease.  

Meanwhile, in her lab, Levy examines how the microbiome influences the development of diseases, like cancer, and other conditions throughout the body.

For instance, a recent study Levy authored identified a number of metabolites (such as breakdown products of food, drugs, or other chemicals) in the vaginal microbiome of pregnant women that could accurately predict whether or not she was at risk for pre-term birth. 

An Emphasis on Collaborating with Clinicians   

While their research is grounded in basic science, Levy and Thaiss were drawn to Penn Medicine because of its worldwide reputation for collaboration between researchers and clinical faculty, and the proximity to the clinic at the Hospital at the University of Pennsylvania, where they can utilize tissue banks and patient populations for small clinical trials to rapidly translate their research to inform clinical practices and develop therapies to help patients. 

For example, a recent publication authored by Levy suggested that the ketogenic diet (high fat, low carbohydrate) causes the production of a metabolite called beta-hydroxybutyrate (BHB), that suppresses colorectal cancer in small animal models. 

Now, Levy is collaborating with Bryson Katona, MD, PhD, an assistant professor of Medicine in the division of Gastroenterology who specializes in gastrointestinal cancers, to investigate whether BHB has the same effect in patients with Lynch syndrome, which causes individuals to have a genetic predisposition to many different kinds of cancer, including colon cancer. These efforts are part of a growing emphasis at Penn on finding methods to intercept cancer in its earliest stages

“It’s remarkable that we were able to quickly take the findings from our animal models and rapidly design a clinical trial,” Levy said. “One of the most exciting aspects of our work is not only making discoveries about how our bodies work on a biological level, but then being able to work with the world’s leading clinical experts to translate these discoveries into therapies for patients.” 

Further, studies led by Levy and Thaiss often utilize human samples and data from the Penn Medicine BioBank, to validate animal model findings in the tissue of human patients suffering from the diseases which they are investigating. 

Together Into the Future 

While Levy and Thaiss pursue different research interests with their labs, they also collaborate often, building on their previous research into what the microbiome does, and its role in the biological processes that keep us healthy. Their long-term goal is to learn about the mechanisms by which the gastrointestinal tract influences disease processes in other organs to treat various diseases of the body using the gastrointestinal tract as a non-invasive entry point to the body. 

“Some of the most common and devastating diseases in humans— like cancer or neurodegeneration – are difficult to treat because they are no existing therapies that can reach the brain,” said Thaiss. “If we can understand how the gastrointestinal tract interacts with other organs in the body, including the brain, we might be able to develop treatments that ‘send messages’ to these organs through the body’s natural communication pathways.” 

“Obviously there is a lot more basic biology to be uncovered before we get there,” added Levy. “Most importantly, we want to map all the different routes by which the gastrointestinal tract interacts with the body, and how that communication happens.”

Levy is currently working with colleagues from the Abramson Cancer Center to further investigate how diets might help the microbiome produce metabolites that can protect a person from developing certain types of cancers, or can help make a patient’s body more receptive to different treatments. 

Similar to her research that found markers in the vaginal microbiome predictive of preterm birth, Levy and colleagues in the Abramson Cancer Center are investigating whether there are any markers in the vaginal microbiome that could predict whether a woman will develop ovarian cancer, and if so, how that might offer a pathway for preventing cancer from developing.  

Levy and Thaiss are also collaborating on a study that investigates the biological mechanisms of long COVID, which could explain how the virus is able to cause long-term symptoms like brain fog and fatigue, long after it has been cleared from the body. 

A Team in Science and Life 

In addition to working together closely in their research, Levy and Thaiss spend much of their spare time together with their five-year-old son and two-year-old daughter. When they’re not in the lab, you’ll find them hiking and exploring national parks as well as remote trekking sites all over the globe.

“We’ve taken our kids on these treks ever since they were small babies, and as they get older, they enjoy it more and more,” said Levy. “We try to go to a new destination each year, and with each trip their excitement about nature grows. These family times are very satisfying.” 


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