Investigating The Microbiome’s Role in Healthy Immune System Development

Humans can’t live healthy lives without microbes. Microscopic organisms (such as bacteria, fungi, and viruses) live on and in our bodies and throughout the world around us. Our bodies exist as holobionts, hosting trillions of microbes in extensive microbial ecosystems. Known as “the microbiome,” these microbes colonize our skin and mucosal surfaces within our bodies (mainly in the intestines).

Microbes co-exist peacefully with their host (e.g., the human body) and help us stay healthy. They serve crucial functions, such as supporting immune system and helping digest food. However, some microbes are not beneficial, and may promote diseases and disorders, or limit the effectiveness of vaccines and other therapies.

In a five-year project funded by the Advancing a Healthier Wisconsin Endowment (AHW), Medical College of Wisconsin (MCW) principal investigator Nita Salzman, MD, PhD (Pediatrics), director of The Center for Microbiome Research, and co-investigator Calvin Williams, MD, PhD (Pediatrics), chief scientific officer of Children’s Research Institute, are exploring the interactions between the microbiome and the human body that contribute to good health, and the interactions that lead to abnormal development and chronic disease.

Through this work, the investigators will develop data that support new disease prevention strategies and helps people live healthier lives.

The Importance of Early Microbiome Interaction with the Immune System

One critical time for establishing good health begins at birth. From there on, a body learns how to interact with and survive in its environment. The developing immune system and the microbiome interact in the earliest years of life to establish a symbiotic and healthy co-existence. If there are disruptions to that process, such as premature birth or an early introduction of antibiotics, there can be severe health consequences impacting the rest of a person’s life.

According to Dr. Williams, “In the last several years, we’re really just appreciating how potent that time is in shaping our capacity for staying healthy. We’re digging deeply into factors that control this essential window of opportunity for the immune system, to understand their role in shaping the environment that must be maintained for a healthy life.”

The microbiome is implicated in many significant health issues Wisconsin residents and people across the U.S. face, such as obesity and inflammatory and autoimmune diseases. Learning how the microbiome functions and co-exists with a person’s immune system is the first step to creating effective strategies to manage many chronic inflammatory disorders.

“Understanding the underpinnings of how bacteria communicate with the host immune system is critical. Without understanding it, we can’t intervene. You can usually treat established diseases, but it’s very hard to prevent them or address their root causes,” said Dr. Salzman.

Investigating Microbiome Interactions During Immune System Development

With funding from AHW, frequent research collaborators Dr. Salzman and Dr. Williams seek to understand how microbiomes establish themselves during immune system development, and to document the role that process plays in a person’s health.

To do this, the investigators focus on how bacteria colonize the gastrointestinal (GI) tract early in life in ways that benefit a person’s long-term health. They are also investigating the impact of early life disruptions to a body’s co-existence with the microbiome, which can lead to later life health challenges such as inflammation and chronic disease.

Their discoveries could make it possible to manipulate the microbiome to enhance health, allowing future therapies to prevent and treat various conditions and diseases. “This is an exciting and new therapeutic frontier. We are uniquely poised to contribute to the health of Wisconsin residents through the successful completion of these studies.”

Their research for this project includes the following work:

• Characterizing how immune systems develop and respond to GI tract bacteria that allow for stable co-existence with microbes
• Investigating how bacteria communicate with our bodies and how our bodies sense and respond to bacteria in our GI tracts
• Exploring the impact of normal and abnormal early life bacteria colonization on lung and gut development

Depiction of the GI tract microbiome

Research Surprises and Discoveries

The project is in its second year, and the MCW investigators have already encountered surprises and discoveries in their initial data.

One of those discoveries came about through Dr. William’s study of regulatory T cells­–a type of white blood cell critical to regulating our immune systems. When examining the absence of a certain gene molecule from the regulatory T cell population in mice at three weeks of life, it was found that most T cells moving through the gut showed signs of activation. This means that they are responding to an antigen and are poised to generate an immune response. This discovery demonstrated how important this molecule is in early life and will be studied further in the project.

Another surprise came in Dr. Salzman’s study of a microbial product, succinate, which is made by members of the microbiome, and which is also found in many foods we eat. As researchers observed, succinate activates a process in the gut that changes the development of cells that line the small intestine, enhancing the growth of specific cell types (notably Paneth cells, which produce small molecules that have antibiotic function). This process changes the whole microbiological landscape in the gut and will be the focus of future research in this project.

What’s Next for Investigators

As the research in this project progresses, investigators look forward to better understanding how the human microbiome is shaped early in life, and what factors will serve as predictors of a healthy outcome.

“It might be too early for therapeutic interventions, but if we could make predictions and then come up with specific therapeutic solutions, that would really be a home run,” said Dr. Williams.