In January 2011 a very interesting paper was published in Physiological Reviews, exploring the role of gastrointestinal permeability, genetics and risk of development of autoimmune diseases.
This abstract explores some of the principle messages in the paper which is also available as a full free text.
It is generally accepted that it is the interplay between environmental factors and specific susceptibility genes that underlies the aberrant immune response responsible for the onset of these diseases. Less than 10% of those with increased genetic susceptibility progress to clinical disease, suggesting a strong environmental trigger in the predisease state.
Environmental factors are also likely affecting the outcome of the process and the rate of progression to disease in those who develop pathological outcomes. One theory is that antigens absorbed through the gut may be involved.
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.
Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products.
A variety of food substances affect the key transporter activities, impacting on tight junction permeability, metabolic enzyme expression, immune functions and so on. Modulation of the intestinal functions by dietary substances is therefore essential to promote health and recovery from related diseases.
Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.
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.