Gluten Ingestion & Gliadin Release
Wheat gluten breaks into gliadin fragments inside the gut lumen.
- 33-mer: Gliadin peptide (resists digestion)
- High: Digestion resistance (proline-rich sequence)
- <30 min: Reaches epithelium (after chewing)
- 0.5–13%: NCGS prevalence (of general population)
Gluten structure
Gliadin and glutenin form gluten's elastic network.
Incomplete digestion
Human enzymes cannot fully break proline-rich gliadin.
Zonulin Release From Intestinal Cells
Gliadin binds CXCR3 receptors, triggering zonulin in susceptible guts.
- CXCR3: Trigger receptor (gliadin binding site)
- Minutes: Response time (after gliadin contact)
- Subset: Responders (not all individuals react)
- Modulator: Zonulin role (tight junction assembly)
Receptor binding
Gliadin binds CXCR3 on epithelial cell surfaces.
Zonulin signal
Bound receptors trigger intracellular zonulin release.
Tight Junctions Loosen Temporarily
Zonulin disassembles junction proteins, widening gaps between cells.
- Claudin/occludin: Protein affected (junction complex)
- Transient: Permeability change (hours, not days)
- Reversible: Gap widening (reseals after exposure)
- Larger: Molecules crossing (peptides and antigens pass)
Junction disassembly
Claudin and occludin proteins pull apart.
Paracellular leak
Larger molecules pass between, not through, cells.
Bloating, Discomfort & Fatigue
Leaked antigens trigger local immune signals causing gut symptoms.
- Bloating: Common symptom (plus fatigue, discomfort)
- Hours: Onset (after exposure)
- Innate immune: Mechanism (not autoimmune)
- None: Villous damage (unlike celiac disease)
Local immune response
Innate immune cells release inflammatory signals.
Symptom pattern
Bloating, fatigue, and discomfort follow, then fade.
Distinct From Celiac Disease
Barrier changes resolve without autoantibodies or villous atrophy.
- Absent: Autoantibodies (no anti-tTG or anti-EMA)
- 0%: Villous atrophy (structure stays intact)
- Not required: HLA-DQ2/DQ8 (unlike celiac genetics)
- Full: Recovery (barrier reseals completely)
No autoimmunity
Non-celiac sensitivity lacks autoantibody production.
Villi remain intact
No flattening or crypt hyperplasia occurs.