If you have not heard of zonulin, you have most likely heard of “leaky gut”, wherein the intestine becomes over permeable to many complex molecules crossing over from the intestine into the blood stream. It is fascinating that there is an interplay between intestinal contents (microbiome and food digestates) and the immune system. There is a key which unlocks the tight junctions of the intestine, increasing its permeability, and that key is zonulin. There is a molecular pathway which regulates the amount of zonulin in concert with gut contents. Under certain conditions zonulin can be overproduced, leading to the “leaky gut”.
Zonulin has been known in the medical literature for twenty years.
Twelve years after the discovery of zonulin’s regulatory role in intestinal permeability, Alessio Fasano described how intestinal permeability can change, either way. This clear image is from his article.
Caption for this figure. “Figure 1.Schematic representation of the zonulin mechanism of action. A. Resting state: During theresting state TJ proteins are angeged in both homophilic and heterophilic protein-proteininteractions that keep TJ in a competent state (TJ) closed as reflected by the complexity ofTJ meshwork shown in the freeze fracture electron microscopy photograph. B. Followingzonulin pathway activation: Zonulin transactivates EGFR through PAR2 (1). The proteinthen activates phospholipase C (2) that hydrolyzes phosphatidyl inositol (PPI) (3) to releaseinositol 1,4,5-tris hosphate (IP-3) and diacylglycerol (DAG) (4). PKCĪ± is then activated (5),either directly (via DAG) (4) or through the release of intracellular Ca2+ (via IP-3) (4a).Membrane-associated, activated PKCĪ± (6) catalyzes the phosphorylation of targetprotein(s), including ZO1 and myosin 1C, as well as polymerization of soluble G-actin in F-actin (7). The combination of tight junction protein phosphorylation and actinpolymerization causes the rearrangement of the filaments of actin and the subsequentdisplacement of proteins (including ZO-1) from the junctional complex (8). As a result,intestinal TJ become looser (see freeze fracture electron microscopy). Once the zonulin signaling is over, the TJ resume their baseline steady state.FasanoPage 7Clin Gastroenterol Hepatol. Author manuscript; available in PMC 2013 October 01.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript “
The 2020 article by Alessio Fasano linked here, describes the role of zonulin in many chronic inflammatory diseases, including autoimmune disorders, such as multiple sclerosis, metabolic disorders such as obesity, intestinal diseases, neuroinflammatory diseases such as major depressive disorder.
Recent events in my life have made knowledge of zonulin come alive for me. It is my belief that the way zonulin works is highly individual, but knowledge of it, and its workings can probably illuminate at least some of what ails each of us.