Does gluten cause overproduction of zonulin in the gut of patients with suspected gluten sensitivity or celiac disease?

Does Gluten Cause Overproduction of Zonulin in the Gut?

Yes, gluten exposure triggers zonulin upregulation and increases intestinal permeability in individuals with celiac disease, non-celiac gluten sensitivity, and even in healthy controls, though the magnitude of response varies by disease state and genetic factors.

Mechanism of Gluten-Induced Zonulin Release

• Gliadin (a component of gluten) contains polyQ peptide fragments that bind to the CXCR3 chemokine receptor on intestinal cells, which activates zonulin upregulation and leads to disassembly of intercellular tight junctions 1
• This zonulin-mediated increase in intestinal permeability occurs as a physiological response to gluten exposure across all individuals, not just those with gluten-related disorders 2
• Zonulin functions as a physiological modulator of tight junction permeability, and its upregulation is centrally involved in the pathogenesis of celiac disease 1

Evidence in Celiac Disease Populations

• Faecal zonulin levels are significantly elevated in pediatric patients with active celiac disease (347.5 ng/mL) compared to healthy controls (177.7 ng/mL) 3
• Following a gluten-free diet, zonulin levels decrease substantially in celiac patients (from 348.5 ng/mL to 157.1 ng/mL), demonstrating the direct relationship between gluten exposure and zonulin production 3
• Ex-vivo intestinal biopsies from patients with active celiac disease demonstrate greater increases in permeability after gliadin exposure compared to celiac patients in remission and healthy controls 2

Evidence in Non-Celiac Gluten Sensitivity

• Serum zonulin levels are significantly elevated in patients with non-celiac gluten sensitivity compared to both healthy controls and patients with IBS-D 4
• Zonulin can differentiate non-celiac gluten sensitivity from IBS-D with 81% diagnostic accuracy, improving to 89% when combined with demographic and clinical data 4
• Patients with gluten sensitivity demonstrate increased intestinal permeability after gliadin exposure that is comparable to those with active celiac disease, and greater than celiac patients in remission 2
• Six months of wheat avoidance significantly reduces zonulin levels, but only in HLA-DQ2/8-positive individuals with non-celiac gluten sensitivity 4

Genetic Modulation of Zonulin Response

• The haptoglobin genotype determines zonulin expression levels, with Hp2-2 carriers overexpressing zonulin (zonulin is identified as pre-haptoglobin 2) 5
• In individuals carrying the Hp2-2 genotype, gluten intake is associated with lower resting energy expenditure and higher inflammatory markers (IL-6, IL-1β) compared to Hp1-1 carriers 5
• This genetic variation explains why some individuals may experience more pronounced metabolic and inflammatory effects from gluten exposure 5

Universal Response Pattern

• Intestinal explants from all groups—active celiac disease, celiac disease in remission, non-celiac gluten sensitivity, and healthy controls—demonstrate increased permeability when exposed to gliadin versus media alone 2
• The magnitude of permeability increase follows this hierarchy: active celiac disease ≥ gluten sensitivity > celiac disease in remission ≥ healthy controls 2

Clinical Implications

• Zonulin measurement (faecal or serum) can serve as a non-invasive biomarker for monitoring intestinal permeability and gluten-free diet adherence in celiac disease 3
• The significant reduction in faecal zonulin levels with increasing duration of gluten-free diet adherence suggests its utility as an additional monitoring tool beyond traditional serology 3
• However, current major gastroenterology guidelines (AGA, ACG, BSG) do not incorporate zonulin testing into standard diagnostic algorithms for celiac disease or gluten-related disorders 6

Important Caveats

• While zonulin upregulation occurs universally with gluten exposure, this does not mean all individuals should avoid gluten—the clinical significance depends on whether symptoms or disease manifestations occur 2
• The obesogenic and inflammatory effects of gluten appear limited to those overexpressing zonulin (Hp2-2 genotype), not the general population 5
• Zonulin testing is not currently part of standard clinical practice for diagnosing celiac disease, which still requires positive serology and duodenal biopsy confirmation while consuming gluten 6