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Inside Tract - Diarrhea: Rounding the bend at last?

Inside Tract Winter 2012

Diarrhea: Rounding the bend at last?

Date: November 15, 2011

Mark Donowitz gives his scientific perspective on the still-worldwide scourge


Donowitz

Roughly 1.3 million children worldwide died last year from diarrhea. “When I first came to Hopkins 20 years ago, it was 12 million,” says gastroenterologist Mark Donowitz, “which seems almost unimaginable.”

But even the lower figure shocks, he says, because it needn’t be that high.

Oral rehydration therapy—the simple packets of salt and sugar solutes that turned the charts around—still saves lives but it’s not without concerns. The world is ready, Donowitz says, for something that addresses diarrhea directly rather than compensates for its dehydration: something grounded in the biology, something that responds to a variety of causes, whether pathogens, genes or a secondary disease.

Now that’s become a possibility.

As an internationally known molecular biologist focusing on the transport proteins that ply the gut’s epithelium—his lab cloned the brush border sodium-hydrogen exchanger, NHE3—Donowitz has had NIH funding for 30 years.

He’s a past president of the American Gastroenterological Association and now directs the Conte GI Core Research Center at Hopkins. That’s one of the coveted NIH-funded programs—in this case for high-level multidisciplinary translational research on digestive disease—that recently opened thanks, in large part, to Donowitz’s efforts.

 Here he discusses the scourge of diarrhea and remedies that lie ahead.

We know oral rehydration saves lives, but you say there’s room for medication as well.

Dehydration, of course, is why children die from diarrhea. And rehydrating solutions counter that. Unfortunately, their use has dropped from 70 percent of reported cases in the Third World to roughly 32 percent. That could be because using them properly is hugely labor intensive for parents in developing countries. And rehydration doesn’t actually decrease diarrhea—a real problem because parents think it’s not working. They stop treating their babies!

So while you’d strongly want to encourage oral rehydration, adding effective drug therapy could make a great difference.

Do you have something in mind? We know you’ve spent decades clarifying the molecular biology of diarrhea.

Yes, we do. Many different diseases produce diarrhea. Even among bacterial or viral causes, host-pathogen interactions vary in unusual ways because the bugs have been around a long time; evolution has let them figure how to tap into our signaling cascades.

We’ve found, however, that they all funnel into the same final pathway to produce diarrhea. So our strategy for therapy is: Target that one.

Elaborate, please, on the final path.

An important element of it is the sodium-hydrogen exchanger (NHE3) that lies in the brush border of intestinal epithelial cells. We’ve put a lot of study into that long protein. It carries out most of the salt (NaCl) absorption in the small bowel.

Interestingly, NHE3’s activity isn’t constant. It increases or decreases during normal digestion. For example, immediately after eating, NHE3 is inhibited, we’ve found. So no salt gets absorbed into intestinal cells and, accordingly, no water. That allows digestive enzymes in the gut to mix freely with food and work efficiently. Of course, at some point NHE3 gets turned on again so you don’t get dehydrated every time you eat.

In most diarrheal disease, however, NHE3 stays inhibited.

So you focus on undoing that?

Yes. We’ve been learning exactly what regulates NHE3. On a gross level, we know it’s hormones and nerve transmitters. But on a finer scale, we’ve found that part of NHE3—its long, receptive “tail”—responds to certain proteins.

Could you make molecules that mimic that fine-tuning in ways you want—for example, stimulate NHE3 and reverse diarrhea? 

We’ve found a peptide that does just that, better than I’d ever imagined. It works in cell cultures, in intact intestine, in an animal model of cholera. It’s on the way to being patented.  And while I’m at it: We’re also optimistic about another potential drug target, the CFTR chloride channel. It works overtime in diarrhea.

What else is on the wish list?

A good model to test potential drugs. The cystic fibrosis folks spent lots to develop animal models of the disease, but unhappily found the models didn’t reproduce its key aspects.

Now, I think, technology might help us out—you can grow a whole piece of human intestine from a single intestinal crypt cell. Our Conte center should let us try that.

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