The discovery of zonulin in coeliac disease
Date: 2016-04-20
Author: Alessio Fasano MD
Access: Public

It is fair to say that the theory that leaky gut contributes to coeliac disease (CD) and autoimmunity in general was initially greeted with great skepticism, partly because of the way scientists thought of the intestines.

It was only an unexpected twist of fate [that led my research team to] discover a new toxin that caused diarrhoea by a previously undescribed mechanism. It changed the permeability of the small intestine by disassembling those supposedly inert tight junctions, an effect that allowed fluid to seep from tissues into the gut.

Indeed, at nearly the same time, a series of seminal discoveries clarified that a sophisticated meshwork of proteins forms the tight junctions, however little information was available on how these structures were controlled. Therefore, the discovery of our toxin, which we called the “zonula occludens toxin” or Zot (zonula occludens is Latin for “tight junction”), provided a valuable tool for clarifying the control process. It revealed that a single molecule, Zot, could loosen the complex structure of the tight junction. We also realised that the control system that made this loosening possible was too complicated to have evolved simply to cause biological harm to the host. V. cholerae must cause diarrhoea by exploiting a preexisting host pathway that regulates intestinal permeability.

Five years after the formulation of this hypothesis, we discovered zonulin, the protein that in humans and other higher animals increases intestinal permeability by the same mechanism as the bacterial Zot. How the body uses zonulin to its advantage remains to be established. Most likely, though, this molecule, which is secreted by intestinal epithelial tissue as well as by cells in other organs (tight junctions have important roles in tissues throughout the body), performs several jobs including regulating the movement of fluid, large molecules and immune cells between body compartments.

The discovery of zonulin prompted us to search the medical literature for human disorders characterised by increased intestinal permeability. It was then that we first learned, much to my surprise, that many autoimmune diseases – among them CD, type 1 diabetes, multiple sclerosis, rheumatoid arthritis and inflammatory bowel diseases – all have as a common denominator aberrant intestinal permeability. In many of these diseases, the increased permeability is caused by abnormally high levels of zonulin. And in CD, it is now clear that gluten itself prompts exaggerated zonulin secretion (perhaps because of the patient’s genetic makeup).

This discovery led us to propose that it is the enhanced intestinal permeability in CD patients that allows gluten, the environmental factor, to seep out of the gut and to interact freely with genetically sensitised elements of the immune system. That understanding, in turn, suggests that removing any one factor of the autoimmunity-causing trinity – the environmental trigger, the heightened immunity or the intestinal permeability – should be enough to stop the disease process.

With several different approaches in the pipeline to treat CD, we can begin to hope that this disease, which has followed humanity from the dawn of civilisation, is facing its last century on earth.

Dr Alessio Fasano presented at the 4th BioCeuticals Research Symposium about the discovery of zonulin, and research into digestive disorders.

To view this presentation please go to


Dr Alessio Fasano, MD

Chief of Division of Pediatric Gastroenterology and Nutrition
Director of Center for Celiac Research and Treatment
Director of Mucosal Immunology and Biology Research Center
Vice Chair, Department of Pediatrics, Basic, Clinical and Translational Research
MassGeneral Hospital for Children
Visiting Professor of Pediatrics, Harvard Medical School

World-renowned pediatric gastroenterologist, research scientist and entreprenuer Alessio Fasano, M.D., founded the Center for Celiac Research in 1996. His visionary research led to the awareness of celiac disease as a growing public health problem in the United States. His prevalence study published in 2003 established the rate of celiac disease at 1 in 133 Americans. In 2000, he and his team discovered zonulin, opening up the door to a new way of looking at the function of intestinal permeability, not only as it affects the gut, but also what role it plays in both inflammation and autoimmunity throughout the systems of the body.

As Visiting Professor at Harvard Medical School and Chief of the Division of Pediatric Gastroenterology and Nutrition at Massachusetts General Hospital, Dr. Fasano moved the Center to Boston in 2013, where he treats both children and adults for gluten-related disorders. A passionate advocate for collaboration in research and clinical work, Dr. Fasano recently authored Gluten Freedom to provide patients, healthcare providers and general readers an evidence-based yet entertaining book to dispel confusion about gluten and how it can affect your health.