number 10 / 2013 lem in the field of hygiene-sanitary safety of raw materials and of the cereal food chain. Deoxynivalenol (also called vomitoxin owing to its effects on the gastrointestinal apparatus) which forms in wheat before being harvested can be frequently found in different types of flour, bread, biscuits, in various cereal containing foods, also destined to very young children, and in industrially-made beer. Its symptoms affect many organs and apparatus; among the symptoms, neurological cytokine ones which are responsible for c.d Sickness like behaviour (chronic inflammation at cerebral level due to IL1β, IL6; TNFα). Clinical findings gave evidence of abnormal intestinal permeability with damage at Claudin 4 of Tight Junction which, in turn, will develop mycotic infestations even with minimum amounts of mycotoxins present in one’s food. At the same time, sensitivity to food antigens and low dose respiration takes place (quantum immunologic). In allergology the connection between food intolerance and leaky gut is by now well known and manifests itself in the hyperactivation of intestinal mast cells which, by releasing histamin and serotonin, increase intestinal permeability which, in turn, deteriorates food intolerance. The release of neuromediators such as P, CRH; NGF (neurogenic inflammation) is responsible for some symptoms such as bloating. Leaky gut is intimately connected to self immune diseases and is in turn maintained by drugs. Single doses of aspirin or indometacin increase intestine wall permeability due to inhibition of anti-inflammatory prostaglandins; such complication can be partly prevented treating patients before with prostaglandin E analogues. Instead, chronic FANS exposition is associated to a condition of chronic irreversible flogosis with misoprostol. In this case some improvement was obtained submitting the patients to antibiotics or metronidazol, thus confirming the importance of bacterial endotoxines in the maintenance the vicious circle. Patients affected by rheumatoid arthritis treated with FANS present high levels of antibodies directed against Clostridium perfrigens and its α-toxin. Moreover, increased intestinal permeability seems to be at the root of some extra-intestinal tumours. As we have seen, the epithelial cells are highly polarised cells and are interconnected by cellular junctures. Mesenchymal phenotype cells, instead, do not establish inter-cellular contacts and have migratory features. Tumour development is correlated to c.d epithelium mesenchymal transition (EMT) which is a key factor of embryonic development; EMT allows an epithelial cell to migrate from the primary tumour site. During EMT the epithelial cells lose intercellular junctures in exactly the same way as in leaky gut. In this case the main marker is not zonulin, but the loss of E-cadherin, an event which is associated to inter-cellular juncture destruction. The increase of N-cadherin, of α-actin of smooth muscle (α-SMA) and of ma-
trix metalloproteases (MMP) are other mesenchymal markers. Therefore, the cells which effect EMT acquire mesenchymal features, which are necessary to migrate from the primary tumour site. TGF-β1 is the EMT inducer par excellance and carries out a fundamental role both in ontogenic processes and in neoplastic transformation. However, in recent studies reactive oxygen species (ROS) have been proven to be capable of inducing EMT as well as generating DNA oxidative damage responsible for genomic instability. EMT is dependent on ROS because in the presence of N-acetylcysteine (NAC, generic “scavenger”) cells do not effect transition. In the presence of NAC the E-cadherin is not lost and the levels of N-cadherin, of α-SMA and of MMP2 do not increase. NAC drastically reduces the activation level of transcriptional factors.
Leaky gut is intimately connected to selfimmune diseases and is in turn maintained by drugs.
Picture 3 Action of guanylate cyclase From the research it emerges that the receptor of the guanylate cyclase C hormone (GC-C) - an already famous suppressor present in the intestinal tract - plays a key role in strengthening the intestinal barrier separating the intestinal environment from the rest of the body. Without the receptor, the barrier gets weaker. The team of Scott Waldman discovered in a pre-clinical study that GC-C silencing in mice compromises intestinal barrier integrity, thus allowing possible cancerous agents - environmental and/or taken with food- to migrate and damage the DNA of external intestinal tissues, too. On the contrary, GC-C stimulation in the intestines of mice strengthened intestinal barrier and prevented contamination of such pathological events. The study paves the way to future pre-clinical and clinical studies aiming at the understanding of the capacity of GC-C in human beings, including the prevention and the treatment of inflammatory intestinal celiac and cancer diseases. In order to prevent intestinal inflammation or certain types of cancer in human beings we will probably have to find the way to intervene on GC-C activating hormones to make the intestinal barrier “thicker”. Also in the ophthalmic field (the conjunctiva is an integrating