Seeing Molecular Explanations for Diarrheal Diseases
Date: August 31, 2010
An astounding variety of illnesses can cause diarrhea. The list ranges from infectious diseases to the extremely rare genetic disorder tricho-hepato-enteric syndrome.
To Johns Hopkins biologist Nicholas Zachos, what’s interesting is what these disparate conditions may have in common. “On a fundamental level,” he says, “diarrhea can occur when the epithelial cells lining the gut do not properly reabsorb water.”
To better understand this mechanism, Zachos is focusing on a protein called NHE3, or sodium/hydrogen exchanger-3. It resides in the epithelial cells that line the gut, specifically in the cells’ apical membrane, the region facing the intestinal cavity. There it shuttles sodium ions from the intestinal cavity into the cell. Where sodium goes, water follows, and this mechanism enables the gut to maintain a proper water and ion gradient.
In past studies, NHE3 has been associated with various diarrheal diseases. While these have largely relied on biochemistry and genetics, Zachos is now using spinning-disk confocal microscopy to watch the protein’s movement in real time.
“In less than a minute,” he says, “it moves from the cell’s apical membrane into a recycling compartment inside the cell.” His studies are revealing how normal cells choreograph this protein shuffle and how it goes awry in various diseases.
Zachos has also used microscopy to examine epithelium from inflammatory-bowel-disease patients. In them he finds that much less NHE3 appears in the apical membrane, though the reason isn’t clear. “Is it the disease that causes the down-regulation, or vice versa?” he asks.
In another study, Zachos, with clinicians from the University of Birmingham School of Medicine in England, studied biopsies from patients with tricho-hepato-enteric syndrome. Babies born with this disease have intractable diarrhea and a host of other health problems, and often die before age 5. Through his microscope, Zachos observed one possible explanation: NHE3 and a related sodium transporter, NHE2, had taken an errant path and were not in their normal positions in the epithelium.
Zachos hopes such studies will lead to potential new therapies for diarrheal diseases. “Our goal,” he says, “is to visualize where NHE3 is going, characterize its path and its activity, and then find drugs that correct for problems that we see.”