Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Abstract

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.

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

“…Zonulin, which can induce tight junction disassembly and increase intestinal permeability, is upregulated in T1D, and gliadin induces zonulin upregulation in the intestinal cell line Caco2 [37]. This may result in direct stimulation of NK cells present in the lamina propia by gliadin or APCs [38,39]. It has also been suggested that gluten peptides might be presented by DCs sampling the intestinal lumen [40], which may increase the crosstalking with NK cells [14], thus making it possible for gliadin to activate NK cells even in the absence of a leaky gut epithelium.…”

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

“…Furthermore, regulation of the exchange of molecules between the environment and the host through the intestinal barrier influences the equilibrium between tolerance and immunity to self and non-self-antigens (Fasano, 2011). From a structural perspective these functions are preserved by a number of features including a mucus layer and a monolayer of epithelial cells interconnected by tight junctions.…”

GUT-the Trojan Horse in Remote Organs’ Autoimmunity

“…Is it a cause, consequence or coevolutional phenomenon? [10,[27][28][29]. Data is accumulating that intestinal luminal environmental factors might perturbate the regulatory mechanisms of the tight junction, resulting in a leaky gut thus breaking equilibrium between tolerance and immunity to nonself-antigens.…”

“…Nutrients, toxins, allergens, carcinogens, intestinal infections, dysbiotic bacteria, drugs and stress and the recently described industrial processed food additives, can breach the tight junction integrity [3,4,[7][8][9][10]12,13,[15][16][17][18]23,24,28,29]. In fact, TJ dysfunction seems to be a primary defect in AD [28][29][30]. Intestinal permeability is increased in many AD: Ulcerative colitis, Crohn's disease, CD, inflammatory joint disease, ankylosing spondylitis, juvenile onset arthritis, psoriatic arthritis, type 1 diabetes mellitus and primary biliary cirrhosis.…”