by Nick Miller

Turns out the old adage, “You are what you eat,” is true - although there is much more to the story.

Researchers have long understood that what we breathe, drink and swallow can play important roles in triggering disease. Now, new research at Cincinnati Children’s is helping explain why our well-being depends so much upon the relationships between what we ingest, the cells lining our intestine, and the trillions of commensal bacteria (normal flora) living there.

Theresa Alenghat, VMD, PhD.

Dr. Theresa Alenghat and colleagues are studying how bacteria interact with mammalian cells in the intestine. Their hope is to uncover new pathways that impact the development of immune-mediated diseases, such as inflammatory bowel disease.

Theresa Alenghat, VMD, PhD, is a researcher in the Division of Immunobiology who was recently named a 2015 Pew Scholar. She is working to decipher the crosstalk that occurs between mammalian cells and bacteria that normally reside in the intestine, whose diversity and location can be affected by factors ranging from diet to medications to emotional stress.

“When I was working on my PhD, whether the intestine could be involved in what we were studying did not cross my mind,” Alenghat says. “Now, as numerous diseases are being linked to intestinal health, it is interesting to see how this mentality has changed. Over the last decade or so we have come to recognize that commensal bacteria and the intestinal microenvironment are essential factors in disease development.”

EPITHELIAL INTERFACE

The epithelial cells lining our intestines do much more than help our bodies absorb nutrients and provide a physical barrier. They also constantly interact with our commensal bacteria, secreting small proteins called antimicrobial peptides and cytokines, which in turn affect bacterial populations and regulate immune cells.

“These epithelial cells are sometimes overlooked, so we are interested in studying how they mediate crosstalk between intestinal bacteria and immune cells to affect health,” she explains.

Research increasingly shows several significant public health challenges – diabetes, allergies, asthma, cancers, autism and inflammatory bowel disease – develop from complex gene-environmental interactions. The mystery is where, why, and how these interactions are triggered. More and more, evidence points to processes that get started in the intestine.

Changes in intestinal bacteria can lead to changes in our epigenome; or the way our genes are turned on and off over time by environmental factors. When all goes well, beneficial bacteria survive in the intestine and send signals that maintain a healthy epigenome. However, environmental exposures that impact commensal bacteria may trigger epigenomic dysregulation, and prolonged exposures can set up a negative cycle that leads to disease.

Alenghat and her colleagues have identified a key factor in how this process works. Histone deacetylase 3 (HDAC3), an enzyme in intestinal epithelial cells, acts as an epigenomic modifier that regulates healthy intestinal function. In mice, deleting HDAC3 from intestinal epithelial cells impaired intestinal function, caused intestinal damage and led to inflammation, according to a 2013 Nature study Alenghat co-authored while at the University of Pennsylvania. The paper showed that HDAC3 integrates signals from commensal bacteria to regulate gene networks, calibrate epithelial cell function, and maintain normal intestinal health.

Intestinal bacteria play larger-than-expected role in health and disease development.

Intestinal bacteria play larger-than-expected role in health and disease development.

NEXT STEPS

With HDAC3 as one focal point, the researchers are teasing out which of the trillions of commensal bacteria are critical to regulating the epigenome. They want to see how intestinal bacteria interact with HDAC3 and its downstream pathways to impact immunity and trigger disease.

The efforts include a collaboration with Lee Denson, MD, Medical Director of the Inflammatory Bowel Center, to study intestinal biopsies from patients with inflammatory bowel disease. If they can detect disease-causing changes in the epigenome and commensal bacteria, it may be possible to develop new ways to improve treatment and predict prognosis.

Alenghat also plans to test how bacterial factors affect intestinal biology by analyzing organoids of human intestinal tissue, a new research tool developed by the laboratory of Jim Wells, PhD, Developmental Biology and Endocrinology. Combining the organoid findings with methods involving unique mouse models that lack commensal bacteria will create a robust system for deciphering the links between the microbiota and intestinal health.

“Multiple studies have come out recently that indicate that the microbiota may be interacting with epigenomic pathways in different mammalian cells,” Alenghat says. “Now that we know this is happening, I think we are just beginning to explore what it all means, how it relates to disease and how this will enable new approaches for managing chronic diseases.”