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Our Tests Gut Health Assessment

Intestinal Permeability

Description/Background Information

Zonulin – the “GateKeeper” of Intestinal Permeability

The intestinal wall—the single-cell-thick layer of epithelial cells lining the inside of the gut—is the largest barrier between the human body and the outside world. Maintaining control of this barrier is crucial for regulation of the immune system and protection against pathogens. There are two routes from gut lumen to the bloodstream—across the enterocyte brush border via transporters (the “transcellular” route, as in absorption of most nutrients), or through gaps between the cells (the “paracellular” route, through which ions, water-soluble molecules, and occasional microbes passively flow). The paracellular route is finely controlled by intricate protein “gates” called tight junctions.1-3 These dynamic structures open and close in tune with dietary state, physical activity, hormonal and neural signals, and inflammatory mediators.4,5

Zolingraphic

A key physiological and reversible modulator of tight junctions is zonulin, a protein produced in the mucosa that directly controls intestinal permeability.2,6,7 In response to stimuli such as luminal bacteria or food-derived triggers (e.g., gluten), zonulin is released into the lumen and binds to receptors on the epithelial cells’ apical surface, activating signaling pathways that cause disassembly of the tight junction.2,6,8-10 This zonulin-driven opening of the paracellular pathway may be a defense mechanism, as it allows secretion of water into the lumen, flushing out microorganisms to prevent their colonization.7

Zonulin, Intestinal Permeability, and Disease

Prolonged zonulin upregulation from environmental triggers can lead to increased intestinal permeability and an uncontrolled flow of intestinal antigens into the submucosa, which can cause chronic inflammation and autoimmune disorders in genetically susceptible individuals—both in the gut (e.g., celiac disease, inflammatory bowel disease) and throughout the body (e.g., type 1 diabetes, rheumatoid arthritis, multiple sclerosis).1,4,11-12

Intestinal hyperpermeability is also associated with chronic conditions of unclear etiology, such as irritable bowel syndrome (IBS).13 Translocation of bacteria (or bacterial products such as lipopolysaccharide) into the circulation plays a causative role in many metabolic conditions, such as fatty liver disease, type 2 diabetes, and cardiovascular disease, by promoting inflammation in the liver.3,14 Gut-derived bacterial products and cytokine cascades resulting from gut barrier breach have also been linked to neuroinflammation and the development of depression.15

Clinical Utility & Indications

Clinical studies have shown that zonulin levels correlate strongly with the “gold standard” lactulose-mannitol test for intestinal permeability.16 Zonulin is thus an excellent biomarker of impaired gut barrier function. There may be advantages to measuring zonulin in stool vs. serum when assessing intestinal permeability, as serum zonulin also reflects its release from other tissues such as lung and brain.6

Increased intestinal permeability has been linked to many chronic conditions, and activation of the zonulin pathway has been implicated in the pathogenesis of celiac disease and metabolic disorders:

  • Zonulin upregulation in patients with celiac disease reflects the increased intestinal permeability that is a key feature of the disorder.2,7 Elevated zonulin in patients with dermatitis herpetiformis who have only minimal mucosal damage suggests an early role for abnormal zonulin-dependent intestinal permeability in the pathogenesis of gluten-dependent diseases.17 Even in nonceliac patients, gluten-derived gliadin has been shown to stimulate zonulin release and increase intestinal permeability.10
  • Elevated zonulin levels have been demonstrated in a substantial proportion of patients with type 1 diabetes (T1D; 42% in one study)17 several years before disease onset. This is consistent with a causative role of intestinal hyperpermeability in autoimmune diabetes and a predictive role of zonulin in disease onset and progression.14,15 Preclinical studies also support a mechanistic role of zonulin-mediated hyperpermeability in the pathogenesis of T1D.19
  • Compromised gut barrier function and increased zonulin levels have been associated with insulin resistance (independent of body mass index), and metabolic conditions such as type 2 diabetes.14,20,21 Here, increased intestinal permeability renders the patient more susceptible to luminal antigens, which may trigger the release of anti-inflammatory cytokines and autoimmune reactions against the beta-cells of the pancreas.14
  • A link between zonulin level, insulin resistance, visceral adiposity, and severity of menstrual disorders in women with polycystic ovary syndrome suggests that zonulin may aid in risk stratification for cardiometabolic disease in such patients.22

Zonulin Cut Points & Interpretation

Optimal Mildly Elevated High
≤ 64.9 ng/g 65-85 ng/g ≥ 85.1 ng/g

The Salveo Diagnostic cut points have been established on the basis of estimated disease prevalence in our validation studies and represent the 80th (85.1 ng/g) and 60th (65 ng/g) percentiles.

  • Zonulin values ≤ 64.9 ng/g suggest healthy tight junctions maintaining appropriate levels of intestinal permeability
  • Zonulin values from 65 to 85 ng/g may represent mild upregulation in zonulin-mediated intestinal permeability
  • Zonulin values ≥ 85.1 ng/g are higher than the 80th percentile, consistent with increased intestinal permeability

References

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  16. Sapone A, et al. Diabetes 2006;55:1443–1449.
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  19. Watts T, et al. Proc Natl Acad Sci 2005;102:2916–2921.
  20. Moreno-Navarrete JM, et al. PLOS One 2012;7:e37160.
  21. Zhang D, et al. Diabetes Res Clin Pract 2014;106:312–318.
  22. Zhang D, et al. Eur J Endocrinol 2015;172:29–36.
  23. Groschwitz KR, Hogan, SP. J Allergy Clin Immunol 2009;124(1):3–20.
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