Innovative research in immunobiology is fueling new insights into the regulation—and possible prevention—of disease

by Tom O’Neill

Theresa Alenghat’s mission is to untangle the good microbes from the bad, and decipher how they regulate our cells.

From their home in our intestinal tract, trillions of microbes, collectively called the microbiota, play a key role in triggering healthy immune responses and disease development. The challenge is determining how these diverse little targets do this.

“There is a lot of the excitement about trying to determine which components of the microbiota are beneficial, and using that knowledge to treat patients and improve health,” Alenghat says.

Now, new research led by Alenghat reveals just how complicated the microbial world is, and how a better understanding of its pathways has the potential to improve treatment of a wide range of diseases. Or even, help prevent them.

Her essential tool: mice devoid of microbes.

These mice have abnormal immune and metabolic responses and can be colonized with single or defined groups of microbes.

“For us, the big questions are: Do different intestinal microbes actually impact our cells in distinct ways? And if so, how do they do this?” says Alenghat, VMD, PhD, of the Division of Immunobiology

Commensal Microbes: From Infancy to Insights

Although research into immune system response is not new, the science of analyzing the good or “commensal” microbes in mice devoid of microbes is a relatively new arena that has taken off over the last decade.

bacterial and intestinal cells interacting.

This confocal image shows bacteria (green) interacting with cells (red) in the intestine. It is from the lab of Theresa Alenghat, VMD, PhD.

Alenghat’s team was the first to bring this innovative approach to Cincinnati Children’s.

Establishing this unique tool involved support from Veterinary Services and the Research Foundation, and took about a year to complete.

“At this point we know that the microbiota are required to support health, and that the types of microbes present can change with disease,” says Alenghat, a 2015 Pew Scholar.

“What we don’t know is which of these microbes do what and how they do it,” she adds. “With these new tools, we are now able to start exploring these questions here.”

The diversity of these microbes is an obstacle for researchers: bacteria, viruses, fungal organisms and parasites among them. There are more than 1,000 different species of bacteria alone.

Researchers believe the microbiota could unlock the mysteries behind many diseases, among them inflammatory bowel disease, asthma, diabetes and obesity.

But the potential is even greater because microbes also regulate essential biological processes such as immunity, metabolism, neuronal development and the formation of new blood vessels.

Microbes Might Play a Role in Educating Cells

 “If commensal microbes promote health and protect against disease, do they do this by educating cells in our body?” Alenghat says. “We think so. Can these educated cells then respond more effectively against infection and prevent abnormal inflammation?”

In a review published in the February 2017 issue of Current Opinion in Immunology, Alenghat and colleagues discussed that epigenetics may underlie how the microbiota may be so instrumental in preventing abnormal inflammation, while simultaneously promoting host defense. 

Short-chain fatty acids appear to be a critical subset of metabolites that come from the microbiota and have the potential to directly modulate the epigenetic landscape. 

However, there are likely many more factors from the microbiota with this function that have not yet been identified.

Microbiota-Epigenetic "Crosstalk"

Theresa Alenghat, VMD, PhD.

Theresa Alenghat, VMD, PhD, (in white lab coat) and Jordan Whitt, a member of the Alenghat lab, prepare supplies that need to be sterilized within specialized gnotobiotic cylinders before being brought to the germ-free room.

Building on recent revelations that the microbiota is instrumental in promoting intestinal immune health, Alenghat’s work focuses on deciphering how epigenetic “crosstalk” helps maintain healthy communication with the microbiota.

Epigenetics involves genes impacted by environmental influences, which in turn change the expression and downstream effects of other genes. This can alter the composition and function of individual cells and help program biological processes that are beneficial or trigger illness.

Alenghat and her colleagues have identified an enzyme in intestinal epithelial cells called histone deacetylases (HDAC3), which acts as a key epigenetic modifier in the intestine.

In a 2013 Nature study, which she co-authored while at the University of Pennsylvania, researchers found that deleting HDAC3 from intestinal epithelial cells of mice resulted in impaired intestinal function and increased inflammation.

That original paper showed that HDAC3 is critical in integrating microbiota-derived signals to calibrate intestinal responses.

This is needed to establish normal host-microbe relationships—and with it, intestinal health.

The study set the groundwork for her current work at Cincinnati Children’s. The Alenghat lab uses her newly established models to decode pathways in our cells that are controlled by epigenetics and different components of the microbiota.

“Uncovering these new pathways will give us deep insight into how our bodies, and these commensal microbes, live symbiotically and why some microbes may be beneficial whereas others may trigger disease,” she says.

Our gut and microbiota didn’t evolve on independent, parallel roads, but as a rather busy intersection unburdened by traffic lights.

“It’s amazing,” Alenghat says, reflecting on her days as a PhD candidate in the mid-2000s, “how much more we now appreciate the intestine and microbiota in regulating diverse aspects of our body, but we are just at the beginning of understanding these complex relationships.”