Leaky gut, leaky brain, and autoimmune disease?
Earlier research by Fasano and colleagues led to the discovery of the human protein zonulin. They observed that zonulin regulates the permeability of the intestines by controlling the opening and closing of specialized structures that act like gates between cells. When the body produces too much zonulin, these gates remain open for too long, allowing undigested foodstuff, toxins and other bacterial and viral particles access to the immune system. That contact, in turn, leads to the production of antibodies that can destroy the insulin-producing islet cells in the pancreas among people genetically predisposed to develop Type 1 diabetes. The final result is the appearance of Type 1, or insulin-dependent, diabetes.
Fasano's group also discovered that zonulin is produced in very large amounts in people who have autoimmune disorders such as diabetes, celiac disease, multiple sclerosis, and rheumatoid arthritis. The researchers performed their latest study on rats genetically prone to develop Type 1 diabetes.
"With autoimmune diseases, the body mistakes its own tissues as foreign, resulting in an attack and destruction by the body's own immune system. These diseases are all characterized by an extremely permeable intestinal wall," says Fasano. "We already knew that there was a distinct connection between an increase in zonulin levels and an increased permeability of the intestines. With this study, we've been able to identify a way to prevent zonulin from causing leakage from the intestines as it does in people with these autoimmune diseases."
"Our current platform is based upon the discovery of zonulin, a paracrine signaling protein that regulates the paracellular permeability of cell barriers throughout the body. Epithelial and endothelial cell layers serve as barriers between body compartments and the environment, maintaining gradients and regulating substance and cellular exchange between these spaces. Physical barrier function is provided by the cells themselves and by a key "gate" that exists between the cells, the tight junction. Found in humans and other mammals, zonulin serves the function of transiently, physiologically and reversibly opening these tight junctions, which are present in barriers as diverse as the intestinal mucosa and the blood-brain barrier."
Alba Therapeutics - Zonulin Technology
Alba Therapeutics Press Releases (check here for up to date releases)
March 17, 2009 - Alba Therapeutics Corporation announced today it will initiate further clinical studies for patients diagnosed with celiac disease with their lead compound, larazotide acetate.
November 11, 2008 - Alba Therapeutics Announces Enrollment of Its First European Patient in Global Phase IIb Study of Larazotide Acetate for Treatment of Active Celiac Disease
October 7, 2008 - Alba Therapeutics Presents New Data for Larazotide Acetate at the 2008 American College of Gastroenterology Annual Scientific Meeting
May 20, 2008 - Alba Therapeutics Announces the Presentation of Results of a Phase IIa Clinical Trial for Larazotide Acetate for the Treatment of Celiac Disease at the Digestive Disease Week Conference
May 16, 2008 - Alba Therapeutics Announces the Enrollment and Randomization of the First Patient in the Phase IIb Clinical Trial for Larazotide Acetate (AT-1001) for the Treatment of Active Celiac Disease
September 19, 2007 - Alba Therapeutics Announces Phase IIb Clinical Trial for Oral AT-1001 for the Treatment of Celiac Disease
September 5, 2007 - Alba Therapeutics Announces Clearance of IND for Beta Cell Preservation in Type 1 Diabetes using AT-1001
May 7, 2007 - Alba Therapeutics Corporation Reports Preliminary Phase IIa Clinical Trial Results for AT-1001 for the Treatment of Celiac Disease. Announces Plans for Advancing AT-1001 into Later Stage Clinical Trials
March 08, 2007 - Alba Announces Completion of Enrollment and Dosing of Patients in Phase II Clinical Trial of AT-1001 for the Treatment of Celiac Disease
November 10, 2006 - Alba Therapeutics Presents Data from Positive Phase Ib Clinical Trial at the XII International Celiac Disease Symposium
January 31, 2007 (UK Times)(pdf) - Could a 'leaky gut' be behind celiac disease?
November 2006 Volume X, Issue 11 - (DOWJONES - Venture Capital Analyst - Health Care Edition) - Celiac Disease: Next Untapped Market?
Zonulin, regulation of tight junctions, and autoimmune diseases.
PMID: 22731712 July 2012
Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.
Leaky gut and autoimmune diseases.
PMID 22109896 Feb 2012
The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a "leaky gut" in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.
Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.
PMID: 21248165 Jan 2011
Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.
Intestinal barrier function: molecular regulation and disease pathogenesis.
PMID: 19560575 July 2009
This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier competency. Understanding the role of zonulin-dependent intestinal barrier dysfunction in the pathogenesis of autoimmune diseases is an area of translational research that encompasses many fields.
Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation. Living Life on the Edge of the Wall.
PMID: 18832585 Oct 2008
There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.
Systemic autoimmune disorders in celiac disease.
PMID: 17053448 Nov 2006
Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non–self antigens, and the development of autoimmunity in genetically susceptible individuals.
Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.
PMID: 16644703 May 2006
CONCLUSIONS: Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.
Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. PMID: 16635908 April 2006
When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function.
Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases.
PMID: 16265432 Sept 2005
Increased intestinal permeability and zonulin up-regulation are common and concomitant findings among patients with DH, likely involved in pathogenesis. Increased permeability can be observed even in patients with no evidence of histologic damage in biopsy specimens.
Permeability, zonulin production, and enteropathy in dermatitis herpetiformis.
PMID: 15822038 April 2005
Combined together, these findings suggest that the zonulin-induced loss in small intestinal barrier function is involved in the pathogenesis of T1D in the BB diabetic-prone animal model.
Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats.
PMID: 15710870 Feb 2005
Intestinal Zonulin: Open Sesame! Aug 2001
Human zonulin, a potential modulator of intestinal tight junctions.
PMID: 11082037 Dec 2000