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Celiac.com 07/30/2019 - Studies have shown increased intestinal permeability in irritable bowel syndrome. Validating serum biomarkers for altered intestinal permeability in irritable bowel syndrome will facilitate research and pathophysiology-based therapy. A team of researchers recently set out to measure serum zonulin and intestinal fatty acid binding protein levels in diarrhea-predominant irritable bowel syndrome and constipation-predominant irritable bowel syndrome, and to compare the results with healthy control and celiac disease subjects. The research team included Prashant Singh, Jocelyn Silvester, Xinhua Chen, Hua Xu, Veer Sawhney, Vikram Rangan, Johanna Iturrino, Judy Nee, Donald R. Duerksen, and Anthony Lembo. They are variously affiliated with the Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America; the Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States of America; and the Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. The team used enzyme-linked immunosorbent assays to measure serum zonulin and intestinal fatty acid binding protein levels in fifty patients with constipation-predominant irritable bowel syndrome, fifty with diarrhea-predominant irritable bowel syndrome, fifty-three with celiac disease, and forty-two healthy control subjects. Using the irritable bowel syndrome-symptom severity scale as a gauge, they found that patients with constipation-predominant irritable bowel syndrome and diarrhea-predominant irritable bowel syndrome had higher zonulin levels compared with healthy controls. They also found that zonulin levels in patients with constipation-predominant irritable bowel syndrome and diarrhea-predominant irritable bowel syndrome are comparable to levels in patients with active celiac disease. The results showed no correlation between zonulin levels and overall irritable bowel syndrome symptom severity. They did, however, show a positive correlation with weekly stool frequency, and unsatisfactory bowel habits in diarrhea-predominant irritable bowel syndrome. Patients with diarrhea-predominant and constipation-predominant irritable bowel syndrome both had lower intestinal fatty acid binding protein levels compared with celiac patients. In patients with irritable bowel syndrome, serum zonulin is upregulated at levels comparable to those for celiac patients, and match the severity of unsatisfactory bowel habits in diarrhea-predominant irritable bowel syndrome. Irritable bowel syndrome patients show no increase in intestinal fatty acid binding protein levels, which likely means no significant increase in enterocyte death. This is an interesting finding regarding serum zonulin levels in some patients with irritable bowel syndrome, as is the positive correlation with weekly stool frequency, and unsatisfactory bowel habits in diarrhea-predominant irritable bowel syndrome. Read more at the United European Gastroenterology Journal; 2019 Jun; 7(5): 709–715. doi: 10.1177/2050640619826419
“Tight junction function” might sound like a song from Schoolhouse Rock, but it’s a topic that explains a great deal about our immune system and the increasing prevalence of autoimmune disorders. The tight junction (TJ) is an essential element of our intestinal structure, and is part of the body’s defenses against bacteria and toxins. About 70% of the body’s immune system resides in the gut, mostly as lymphatic cells. To prevent the immune system from being overtaxed, the TJ restricts access to these cells. The TJ is a matrix of interlocking proteins that open and close tiny pores between cells. The proteins form a hexagonal pattern, similar to chicken wire. Substances can pass through the intestinal wall, either through cell membranes, or between cells, using a the pores (gaps in the chicken wire). Pores help the body absorb nutrients, but must be selective. They use an electrostatic charge to filter out large particles, and to bind cells close together. Zonulins are messenger proteins that signal the pores to open. When zonulins are released, they bind to specific chemical receptors in the intestinal wall. These receptors tell the body to add a phosphoryl group to one of the proteins in the matrix. This deactivates the protein, disassembling the TJ’s hexagonal structure (like cutting a strand of the chicken wire.) The lymphatic cells address molecules that pass through the TJ, and may mark them as antigens (dangerous substances). The “danger” flag may go up on molecules larger in size than the normal dimension of the pores (typical of bacterial infections), known toxins, or a sudden flood of material that is new to the lymphatic cells in the gut. The immune system remembers each antigen and attacks it when it reappears. While this is an effective way to keep out bacteria and toxins, the problem is overkill. When the TJ is leaky (TJ dysfunction is also known as “leaky gut”), the body attacks all substances marked as antigens, even otherwise benign foods. This stresses the immune system, creating inflammation. Inflammation damages the TJ further, loosening it to admit new substances. This creates a vicious cycle, making the TJ even more permeable. This explains why Celiacs who recently had a gluten exposure tend to become sensitive to other foods they are eating during the time they are suffering from leaky gut. Those foods are passing through the loosened pores, and being marked as antigens. But why do the TJs fail to begin with? Everyone releases some zonulin in response to gluten, but those with a gene for Celiac disease release far more zonulin (two standard deviations above the norm, well beyond coincidence). Bacterial infections can also trigger zonulin release. Some industrial food additives are also zonulin triggers. They include nanoparticles (such as titanium dioxide – check your toothpaste and chewing gum ingredients), microbial transglutaminase (“meat glue”), salt nanowires, organic solvents, and emulsifiers. These new ingredients are increasingly common in the U.S. food supply. If they sound inscrutable, it’s for good reason; they’re not naturally occurring. Elevated zonulin levels and TJ permeability are associated with Celiac disease and Type 1 Diabetes. (A drug that reduces zonulin production also protects against damage to insulin-producing cells in Type 1 Diabetes patients.) Overproduction of zonulin is also found in those with Crohn’s disease, schizophrenia, and chronic kidney disease, and other disorders. The intestinal tight junction, and damage to it, is strongly associated with various autoimmune diseases. We are just beginning to understand the role of this important system in modulating health, and the factors that cause it to fail. Sources Anderson, J.M., and C.M. Van Itallie. (2009). Physiology and function of the tight junction. Cold Spring Harb Perspect Biol; 1:a002584. doi: 10.1101/cshperspect.a002584 Brandner, J.M., M. Zorn-Kruppa, T. Yoshida, I. Moll, L.A. Beck, and A. De Benedetto. (2015). Epidermal tight junctions in health and disease. Tissue Barriers 3:1-2, e974451; January-June 2015. doi: 10.4161/21688370.2014.974451 Fassiano, A. (2012). Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012 July; 1258(1): 25–33. doi:10.1111/j.1749-6632.2012.06538.x Khaleghi, S., J.M. Ju, A. Lamba and J.A. Murray. (2016). The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Ther Adv Gastroenterol 9(1): 37–49. doi: 10.1177/1756283X15616576 Lerner, A., and T. Matthias. (2015). Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmunity Reviews 14 (2015) 479–489. doi:10.1016/j.autrev.2015.01.009 Vighi, G., F. Marcucci, L. Sensi, G. Di Cara, and F. Frati. (2008). Allergy and the gastrointestinal system. Clinical and Experimental Immunology, 153 (Suppl. 1): 3–6. doi:10.1111/j.1365-2249.2008.03713.x