Zinc Ameliorates Intestinal Barrier Dysfunctions in Shigellosis by Reinstating Claudin-2 and -4 on the Membranes.

Whether zinc(Zn2+ ) regulates barrier functions by modulating tight junction (TJ) proteins when pathogens such as Shigella alter epithelial permeability is still un-resolved. We investigated the potential benefits of Zn2+ in restoring impaired barrier function in vivo in Shigella infected mouse tissue and in vitro T84 cell monolayers. Basolateral Shigella infection triggered time dependent decrease in trans-epithelial resistance (TER) followed by an increase in paracellular permeability of FITC-labelled dextran and altered ion selectivity. This lead to ion and water loss into the intestinal lumen. Immunofluorescence studies revealed redistribution of claudin-2 and -4 to an intracellular location, and accumulation of these proteins in the cytoplasm following infection. Zn2+ ameliorated this perturbed barrier by redistribution of claudin -2 and -4 back to the plasma membrane and by modulating the phosphorylation state of TJ proteins through ERK1/2 dependency. Zn2+ prevents elevation of IL-6 and IL-8. Mice challenged with Shigella showed that oral Zn2+ supplementation diminished diverse pathophysiological symptoms of shigellosis. Claudin-2 and -4 were susceptible to Shigella infection resulting in altered barrier function and increased levels of IL-6 and IL-8. Zn2+ supplementation ameliorated this barrier dysfunction, and the inflammatory response involving ERK mediated change of phosphorylation status for claudin-2 and -4. Thus, Zn2+ may have potential therapeutic value in inflammatory diarrhea and shigellosis.