UA Steele Center Investigators Discover Answers to Deadly Diarrhea

<p>Fayez K. Ghishan, MD, director of the Steele Children's Research Center, and Pawel Kiela, PhD, research associate professor, are investigating why diarrhea can be so deadly.</p>

Pawel Kiela, PhD and Fayez K. Ghishan, MDTUCSON, Ariz., -- The numbers are staggering and heartbreaking: Each year about 5 million children under the age of 5 die from diarrhea, one of the most widespread and pervasive health problems in underdeveloped nations and the leading cause of childhood deaths worldwide.

With a $1.8 million grant from the National Institutes of Health (NIH), researchers at the Steele Children’s Research Center at The University of Arizona College of Medicine are working to address this health crisis.

Fayez K. Ghishan, MD, director of the Steele Children’s Research Center, and Pawel Kiela, PhD, research associate professor, are investigating why diarrhea can be so deadly. “What we have discovered in the lab is of enormous significance and answers the question of why so many children die from diarrhea,” Dr. Ghishan says. [M]

Most children (and adults) are plagued by acute diarrhea a few times each year. We’re all familiar with the unwelcome symptoms: abdominal pain and cramping, bloating, nausea and loose bowel movements. Individuals with gastrointestinal disorders like celiac disease, ulcerative colitis and Crohn’s disease frequently struggle with inflammatory-associated chronic diarrhea. Diarrhea occurs because the intestines cannot absorb salt. Caused by bacteria, viruses, parasites, medications, functional bowel disorders and food allergies, diarrhea typically is treated by drinking ample amounts of electrolyte-rich liquids to provide essential salts and nutrients. Normally, diarrhea is resolved within a few days, although some conditions that cause chronic diarrhea require medical treatment.

For children living in sanitary conditions with clean water and plenty of food, diarrhea is easily treated. However, because so much of the water in the Third World is contaminated, most of the population is exposed to disease-carrying bacteria. Malnutrition leaves children weakened, making them especially susceptible to infection from tainted water or other means. And the immune systems of very young children are not completely developed, so when they get diarrhea, it quickly can develop into a dangerous condition.

The epithelial lining. Image on left shows the lining when NHE-3 is not inhibited, and the image on the right shows bacteria (in red) leaking through the lining when NHE-3 is inhibited.

“Severe diarrhea can lead to death in a matter of days — from dehydration or sepsis resulting from highly inflamed intestines,” Dr. Kiela says.

Discovery through research
Drs. Ghishan and Pawel are working at the basic-science level to understand what happens in the GI tract during severe diarrhea.

Individuals have nine sodium-hydrogen exchangers, or “transporters,” known as NHE (Na-H-Exchanger). NHEs are proteins responsible for transporting sodium across the GI tract for absorption. “The classic premise to explain diarrhea is that inflammation inhibits the sodium-hydrogen transporters’ ability to move salt through the GI tract. Thus, your intestines cannot absorb salt and this is why you get diarrhea,” Dr. Ghishan explains.

Drs. Ghishan and Kiela have documented new findings about the role of NHE-3, one of the nine sodium-hydrogen transporters. It is well known that NHE-3 is the predominant sodium-hydrogen transporter responsible for the majority of sodium transport across the GI tract. “When the intestines become inflamed, NHE-3 becomes inhibited, so it can’t move sodium through the GI tract, resulting in diarrhea,” Dr. Kiela says.

“But there is more,” Dr. Ghishan explains. “Our research has revealed that NHE-3 has a role beyond that of transporting salt to the GI tract for absorption. We found that NHE-3 is involved in the integrity of the epithelial lining — the cellular structure that creates the intestinal wall, which separates the gut from the bloodstream. We discovered that when NHE-3 is inhibited, or ‘knocked down’ by inflammation, the intestinal wall is breached, the gut becomes leaky, and bacteria escape from the intestines into the bloodstream. Consequently, sepsis likely develops, which may cause death,” he explains. “This is why so many children die. The inhibition of NHE-3 loosens the tightly woven fabric of the intestines. This is the mechanism of action for why the gut becomes leaky. Now, the task before us is to identify compounds that will restore NHE-3, so that the epithelial layer can be restored, reducing the deadly effects of diarrhea,” Dr. Ghishan says.

“Our research not only sheds new light on the function of this important sodium-hydrogen transporter, but also suggests that NHE-3 should be considered in future therapeutic approaches to diarrhea and disorders that cause chronic diarrhea,” Dr. Kiela says.