(08-02-14) Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

ALESSIO FASANO
Mucosal Biology Research Center and Center for Celiac Research, University of Maryland School of Medicine, Baltimore, Maryland
I. Introduction 151 II. Intestinal Barrier and Its Regulation 152 III. The Zonulin System 152 A. Identification of zonulin as pre-haptoglobin 2 152 B. Evolutionary and structural biology of HPs 154 C. Structural characterization of zonulin and its subunits 155 D. Zonulin functional characterization 155 E. Zonulin signaling 156 F. Stimuli that cause zonulin release in the gut 157 G. Zonulin and immunoglobulins have a common ancestor but are distinct molecules 159 H. Zonulin is upregulated in the intestinal mucosa of celiac disease patients 160 IV. Intestinal Permeability and Disease 160 V. Role of Zonulin in Autoimmune, Inflammatory, and Neoplastic Diseases 161 A. Specific diseases in which zonulin involvement has been proven 161 B. Other possible roles for zonulin 167 C. Diseases in which zonulin has been identified as a biomarker 168 VI. Conclusions 170

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.
CONCLUSIONS
The gastrointestinal tract has been extensively stud- ied for its digestive and absorptive functions. A more attentive analysis of its anatomo-functional characteris- tics, however, clearly indicates that its functions go well beyond the handling of nutrients and electrolytes. The exquisite regional-specific anatomical arrangements of cell subtypes and the finely regulated cross-talk between epithelial, neuroendocrine, and immune cells highlights other less-studied, yet extremely important, functions of the gastrointestinal tract. Of particular interest is the regulation of antigen trafficking by the zonulin pathway and its activation by intestinal mucosa-microbiota/gluten interactions. These functions dictate the switch from tol- erance to immunity and are likely integral mechanisms involved in the pathogenesis of inflammatory and neo- plastical processes. The classical paradigm of inflammatory pathogenesis involving specific genetic makeup and exposure to envi-
ronmental triggers has been challenged recently by the addition of a third element, the loss of intestinal barrier function. Genetic predisposition, miscommunication be- tween innate and adaptive immunity, exposure to envi- ronmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer. This new theory implies that once the pathological pro- cess is activated, it is not auto-perpetuating. Rather, it can be modulated or even reversed by preventing the contin- uous interplay between genes and the environment. Since zonulin-dependent TJ dysfunction allows such interac- tions, new therapeutic strategies aimed at reestablishing the intestinal barrier function by downregulating the zonulin pathway offer innovative and not-yet-explored approaches for the management of these debilitating chronic diseases.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: A. Fasano, Univ. of Maryland School of Medicine, Mucosal Biology Research Center, Health Science Facility II, Rm. S345, 20 Penn St., Baltimore, MD 21201 (e-mail: [email protected]).
GRANTS
Some of the data presented in this review were generated with the partial supports of the National Institutes of Health Grants DK048373, DK078699, and AT004089 (to A. Fasano).
DISCLOSURES
A. Fasano has a financial interest in Alba Therapeutics.
REFERENCES : 186 voci bibliografiche

Source: Fasano A. Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. Physiol Rev 91: 151–175, 2011; doi:10.1152/physrev.00003.2008.—

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