Intestinal zonulin: open sesame!

Open Access
Publisher Website
Google Scholar
Abstract
In recent years much has been discovered about the structure, function, and regulation of TJs. However, the precise mechanism(s) through which they operate is still incompletely understood. Several microorganisms have been shown to exert a cytophatic pathological effect on epithelial cells that involves the cytoskeletal structure and TJ function in an irreversible manner. These bacteria alter the intestinal permeability either directly (that is, EPEC) or through elaboration of toxins (that is, Clostridium difficile, Bacteroides fragilis).14 A more physiological mechanism of regulation of TJ permeability has been proposed for the zonula occludens toxin (Zot) elaborated byVibrio cholerae. 15 , 16 Zot possesses multiple domains that allow a dual function of the protein as a morphogenetic phage peptide for the Vibrio cholerae phage CTXφ and as an enterotoxin that modulates intestinal TJs.17 The discovery of Zot has shed some light on the intricate mechanisms involved in the modulation of the intestinal paracellular pathway. Zot action is mediated by a cascade of intracellular events that lead to a protein kinase C (PKC)α dependent polymerisation of actin microfilaments strategically localised to regulate the paracellular pathway (fig 1).18 The toxin exerts its effect by interacting with a surface intestinal receptor whose distribution varies within the intestine, being detectable in the jejunum and distal ileum but not in the colon, and decreasing along the villous-crypt axis.19 This receptor distribution coincides with the regional effect of Zot on intestinal permeability19 and with the preferential F-actin redistribution induced by Zot in the mature cells of the villi.18 These data also suggest that expression of this receptor(s) is upregulated during enterocyte differentiation. This hypothesis is supported by the observation that human intestinal epithelial CaCo2 cells (that resemble the mature absorptive enteric cell of the villi), but not crypt-like T84 cells, express this receptor(s) on their surface.20 The paucity of Zot binding in the crypt area may also reflect the fact that this region is already leaky compared with the more mature epithelium of the tip of the villi21 and thus might not need to express a significant amount of a putative receptor(s) involved in TJ regulation.