ackground and Objectives: Non-celiac gluten sensitivity (NCGS) is a syndrome characterized by gastrointestinal and psychiatric symptoms triggered by wheat consumption of gluten, a protein network in wheat. This condition is distinct from celiac disease and wheat allergy. Although anti-gliadin IgG (AGA IgG) antibody is a candidate biomarker for NCGS, diagnostic criteria remain unestablished and many aspects of gluten sensitivity are still unclear. Our 2026 study at Hyogo Medical University's specialized NCGS outpatient clinic suggested that AGA-IgG alone is insufficient for an accurate clinical evaluation. Therefore, this study evaluated the relationships between AGA IgG, inflammatory biomarkers and both physical and psychiatric symptoms in NCGS patients.
Methods: We evaluated 55 outpatients with NCGS presenting with wheat-induced symptoms and 32 age- and sex-matched healthy controls. Plasma levels of AGA IgG, inflammatory cytokines (IL-22, IL-6, IL-18) and associated proteins (FABP2, zonulin) were measured. Physical symptoms, psychiatric symptoms (depression and anxiety), abdominal symptom-related QOL, and overall physical/mental health were assessed using PHQ-15, PHQ-9, GAD-7, IBS-QOL, and SF-36, respectively.
Results: Logistic regression analysis showed that elevated plasma levels of zonulin and IL-18 were significantly associated with AGA-IgG positivity. Furthermore, higher plasma zonulin levels were significantly associated with AGA-IgG positivity, increased severity of depression (PHQ-9) and anxiety (GAD-7), and lower abdominal QOL (IBS-QOL), even after controlling for age and sex.
Conclusions: In NCGS, AGA-IgG positivity was associated with zonulin, an inflammatory-related protein, and IL-18, an inflammatory cytokine reflecting intestinal permeability pathology. Gluten ingestion in these patients is suggested to trigger zonulin-mediated barrier disruption, promoting antigen penetration and systemic immune responses. Furthermore, beyond local gut inflammation, this barrier dysfunction and subsequent immune responses may be linked to depressive symptoms, anxiety, diminished abdominal symptom-related QOL, and overall QOL.