Zonulin acts as the gate-keeper between the cells of the intestinal lining in order for nutrients and other essential molecules to be transported in and out of the intestine. However, when leaky gut is present, the intestinal lining is compromised allowing larger protein molecules to get into the bloodstream thereby causing an immune response.

Intestinal Permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. One way in which intestinal permeability is modulated is via CXCR3 receptors in cells in the intestinal epithelium, which respond to zonulin. Gliadin (a glycoprotein present in wheat) activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules. The cytoskeleton is also made up of proteins, which comprise a network of thin, overlapping fibers known as the actin-myosin network. This partnership between the actin-myosin network proteins controls the permeability of the tight junctions, and thus the intestinal barrier.