Circulating levels of zonulin is a clinically useful marker of intestinal permeability. Zonulin is a protein, synthesized in intestinal and liver cells, that reversibly regulates intestinal permeability. High levels of zonulin have been associated with increased intestinal permeability, as zonulin induces the breakdown of the tight junctions between intestinal epithelial cells. Several autoimmune, inflammatory, and neoplastic diseases have been associated with elevated levels of zonulin or evidence of increased intestinal permeability. These include celiac disease, type 1 diabetes, and juvenile nonalcoholic fatty liver disease. In addition, eveidence is accumulating to support an association with multiple sclerosis, rheumatoid arthritis, asthma, and inflammatory bowel disease.
Zonulin levels may be higher in obese adults and in adults with glucose intolerance. Elevated serum levels of zonulin and increased permeability are commonly observed in patients at risk of developing Crohn’s disease or type 1 diabetes prior to the onset of symptoms. Zonulin levels may increase with corticosteroid use.
Cellular receptors for zonulin are present in the small and upper large intestines, the heart and the brain. Zonulin release from the epithelium may be triggered by gliadin fragments or by the adherence of bacteria to the epithelial cell surface. Simple sugars, sodium, emulsifiers, the food additive microbial transglutaminase, and nanoparticles are known to disrupt intestinal barrier function.
Restoration of the gastrointestinal mucosal barrier may include dietary changes, treatment of dysbiosis, digestive supports, and anti-inflammatory therapies. These may include supplements such as quercetin, vitamin C, curcumin, gamma-linoleic acid, omega-3 fatty acids (EPA, DHA), and aloe vera. Other nutrients such as zinc, beta-carotene, pantothenic acid, and L-glutamine may provide some support for rejuvenation of the GI mucosa. Consider a Comprehensive Stool Analysis to further investigate potential causes of increased intestinal permeability.
Zonulin expression in the small intestine occurs when a chemokine receptor is stimulated by gliadin or chemokines and induces proinflammatory signaling pathways in gastrointestinal epithelial cells. The released zonulin activates the cell-signaling pathway via protease-activated receptor 2 and epidermal growth factor, which causes disassembly of the tight junctions between the GI epithelial cells. The loss of the tight junctions increases intestinal permeability and allows polypeptides and other macromolecules to pass between epithelial cells into the lamina propria layer of the gut wall. The macromolecules and polypeptides induce and antigen response and promote proinflammatory cytokine production in the enteric immune system.
Zonulin is a prehaptoglobulin- levels are modulated by the presence or absence of haptoglobin (HP) gene. When zonulin is cleaved by intestinal tryptase IV, it is converted into haptoglobulin, a protein with heme (iron)-binding and antimicrobial properties. HP-1-1 genotypes have zero (null) copies of the HP gene. HP-2-2 genotypes have 2 copies of the gene, and HP-1-2 genotypes have 1 copy of the gene. HP 1-1 (null) genotypes may have zonulin levels in the normal range, even if the presence of inflammatory or autoimmune disease is confirmed by other biomarkers. Zonulin levels may increase in nephrotic syndrome (HP 2-1 or 2-2 genotypes). In recent years, scientists have identified zonulin as a key biomarker for intestinal permeability, which has been associated with celiac disease, non-celiac gluten sensitivity, and other GI and systemic conditions.
In a healthy GI tract, the tight junctions between cells prevent unregulated influx of luminal contents. However, certain situations, such as the presence of gluten can lead to high levels of zonulin in the GI tract. This can induce the breakdown of the tight junctions, leading to intestinal permeability and allowing zonulin to enter the bloodstream [see also Leaky Gut]. As a result, circulating zonulin is a clinically useful marker of intestinal permeability. What’s more, zonulin is the only regulator of intestinal permeability known to be reversible, which makes it valuable in monitoring therapeutic interventions as well. Several autoimmune, inflammatory and neoplastic diseases have been associated with elevated levels of zonulin or evidence of increased intestinal permeability, which can be identified by the serum zonulin test.
Courtesy of Doctor’s Data