Modulation of the intestinal tight junctions using bacterial enterotoxins

This chapter discusses the modulation of the intestinal tight junctions using bacterial enterotoxins. Epithelial cell sheets limit the movement of solutes through the intercellular space by forming tight junctions (tjs) between adjacent epithelial cells, and therefore act as the major barrier between the internal and external environment of the body. There are three transepithelial pathways for molecules to pass from the intestinal lumen to the bloodstream: the passive transcellular pathway, the carrier-mediated transcellular pathway, and the paracellular pathway. Physicochemical properties, such as hydrophobicity, allow a molecule to passively partition from the intestinal lumen through the lipid bilayer into the cell. Some hydrophilic molecules, such as sugars and amino acids, are absorbed by specifically interacting with active transport systems on the cell membrane. Drug delivery via the paracellular pathway is less dependent on the physicochemical properties of the drug, and does not require a specific interaction with a transport system, and so is suitable for a large variety of molecules including peptides and proteins. Since opening of the tjs can cause the influx of other foreign substances, absorption enhancers acting via the paracellular pathway are required to modify the tight junctional structure reversibly. Early development of paracellular absorption enhancers was limited due to the lack of knowledge regarding the composition of the tjs and their regulatory role, resulting in unacceptable side-effects. Study of canonical enterotoxins (a class of exotoxin that acts on the intestinal epithelium) such as those released by Clostridium perfringens and Vibrio cholerae has increased our understanding to the point where one can exploit their mechanisms to facilitate peptide and protein delivery via the paracellular pathway