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“For this reason, leaky gut syndrome, or the condition caused by increased intestinal permeability, has been vilified by the medical profession.” No matter what the terminology, Fasano and other researchers postulate that this impaired gut barrier function, along with genetic factors and environmental triggers, plays a key role in the development of several chronic inflammatory diseases, including celiac disease. Findings from the paper by Fasano and Craig Sturgeon, PhD, released April 19, 2017, in the Annals of the New York Academy of Science, definitively link zonulin to the development of an inflammatory disease. After treating both zonulin-type mice and normal mice with an agent that produces inflammation in the colon, they measured intestinal permeability. Results show that the zonulin-type mice had a much higher rate of intestinal permeability as well as increased illness and mortality. “This is the first time that we have been able to mechanistically link a zonulin-dependent modulation of gut permeability and enhanced antigen trafficking (a foreign substance producing an immune response) to the development of an inflammatory disease,” says Fasano. The data presented by Fasano, Sturgeon and Jinggang Lan, PhD, lines up with their hypothesis that the presence of the zonulin gene isn’t enough to cause disease. But add two copies of the zonulin gene to a pro-inflammatory stimuli, such as a colitis-inducing treatment, and it increases morbidity and mortality through loss of the intestinal barrier function and increased antigen trafficking. “An even more remarkable finding,” adds Fasano, “is that adding a zonulin inhibitor to the drinking water of the mice completely returned the zonulin mice, which had previously shown chronic inflammation, to an inflammatory rate similar to normal mice—and it completed prevented mortality in the zonulin mice.” The zonulin inhibitor they used was larazotide acetate, or AT1001, a therapeutic agent for celiac disease developed by Fasano while at the University of Maryland School of Medicine in the 1990s. Fasano was once scientific advisor to the startup company that developed larazotide acetate, Alba Therapeutics Corporation of Baltimore, MD. He is no longer involved in the enterprise, which has been taken over by Innovate Biopharmaceuticals of Raleigh, N.C. The zonulin-blocking agent, renamed INN-202 by Innovate, is scheduled to go into Phase III clinical trials sometime in 2017, according to the company website. Given a “path forward” agreement from the Food and Drug Administration, it could be the first drug approved for treatment for people with celiac disease. Fasano still owns stock in Alba Therapeutics, Inc. Sturgeon, co-author of the April 2017 paper and a graduate student who relocated from Maryland to MGH with Fasano in 2013, has his own tale to tell about zonulin mice. “We lucked into finding this animal model,” he says. “We got them from a group in Israel that created them to study the effect of haptoglobin-2 and heart function.” Zonulin is a precursor of haptoglobin-2, a protein that binds hemoglobin to prevent oxidative stress. The three original mice pairs came from the lab of Andrew Levy, MD, PhD, professor of cardiovascular biology at the Rappaport Family Institute for Research in the Medical Sciences in Haifa, Israel. Pest control company seeing more service calls for ticks“When Alessio discovered pre-habtoglobin-2 (zonulin) in 2000, we thought these mice would make a useful tool for studying zonulin in animal models,” says Sturgeon.
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