BY Nathan Collins
For the several million Americans who suffer from celiac disease — a swelling of the small intestine triggered by gluten proteins, with far-reaching consequences including anemia, rashes, and even neurological problems — doctors have only one treatment: never, ever eat gluten ever again.
Still, there is hope for something better. According to a study published last week in the Journal of Biological Chemistry, researchers have now discovered a way to turn off a potential trigger of inflammation for those with the disease, a finding that could one day lead to better treatments.
At the heart of the matter is an enzyme called transglutaminase 2 or simply TG2, which is present throughout our bodies both inside and outside cells, but usually in an inactive form. Although TG2's exact role in celiac disease remains unclear, it's thought that active TG2 outside of cells transforms gluten into a much more potent inflammatory trigger. That observation led to two questions, says the new study's lead author and recent Stanford graduate, Michael Yi, PhD: what turns TG2 on in celiac disease, and what turns it off?
Chaitan Khosla, PhD, a professor of chemistry and director of Stanford ChEM-H, and his lab found an answer to the first question in 2011, when they reported the discovery of a molecule that switched TG2 from its inactive to active state. Then, Khosla, Yi, and colleagues started to look for the off switch.
"We likened it to a fishing expedition at first," Yi says, but they were able to narrow the search based on what they'd learned about TG2's on switch from the 2011 study, and now, they say, they found the off switch. That finding could help them develop drugs that keep celiac disease in check with less severe lifetime dietary restrictions, although Yi remains cautious.
"The study we conducted is very preliminary because we were only working with cells" outside the body, Yi says, rather than inside a living organism. The next step will be to test the idea in mice — something of a challenge, since there is not a particularly good mouse version of celiac disease on which to test the TG2 switch — with tests in humans farther down the line.
Still, Khosla says his lab is moving forward. "Michael's mechanism has given us a clue for how to look for a new kind of drug candidate" that would help flip the celiac switch, and the lab is preparing to test a few "interesting molecules," Khosla says. "This is a good example of how understanding a basic molecular mechanism can point to therapeutically relevant research directions."