¹Hyogo Medical University, Department of Neuropsychiatry, Nishinomiya, Japan

Background: Gluten intolerance is a syndrome characterized by several physical and psychological symptoms such as abdominal pain, constipation, diarrhea, headaches, brain fog, fatigue, anxiety, and depression associated with gluten consumption. Gluten intolerance is one of the gluten-related disorders and is thought to have a different mechanism from autoimmune diseases such as celiac disease and allergies. Diagnostic criteria for gluten intolerance have not yet been established, and many aspects of gluten sensitivity remain unclear. Hyogo Medical University established a specialized outpatient clinic for gluten intolerance in 2019 and has been conducting medical treatment and research. We have previously reported that patients with immunological gluten sensitivity (anti-gliadin IgG antibody positive) were found at a higher frequency in patients with treatment-resistant schizophrenia and depression than in healthy controls. Furthermore, we have already reported the sensitivity and specificity of anti-gliadin IgG antibodies as a biomarker for gluten intolerance at CINP2025, suggesting that it may be necessary to combine anti-gliadin IgG antibodies with other markers such as inflammatory cytokines and related proteins. It has been suggested that gluten intolerance may be a factor in the worsening of various mental disorders, and the relationship between these markers and physical/mental symptoms remains unclear.

Aims & Objectives: The aim of this study was to investigate whether inflammatory cytokines and inflammatory-related proteins are associated with immunological gluten sensitivity, and to examine their relationships with physical and psychiatric symptoms in patients with gluten intolerance.

Method: We measured the inflammatory cytokines IL-22, IL-6, IL-18, and the related proteins FABP2 and zonulin, and investigated their association with psychiatric and physical symptoms among patients who visited our outpatient gluten intolerance clinic, 20 who were immunologically gluten-sensitive positive (anti-gliadin IgG antibody positive) and 37 healthy controls matched for age and gender. Psychiatric and physical symptoms were assessed through medical interviews and self-administered questionnaires. This study was approved by the Hyogo Medical University Ethics Committee. A detailed explanation of the research procedure was provided to each participant when obtaining informed consent.

Results: In immunologically gluten-sensitive individuals, zonulin and IL-18 were significantly higher compared to the healthy control group (P = 8.3 x 10⁻⁶, 3.1 x 10⁻³, respectively). No significant differences were observed between the two groups for IL-22, IL-6, or FABP2. Preliminary investigations found no correlation between IL-18 and psychiatric symptoms, but zonulin measurements showed significant negative correlations with physical QOL, mental QOL, and overall IBS-QOL scores.

Discussion & Conclusions: Immunological gluten sensitivity was associated with IL-18, an inflammatory cytokine, and zonulin, an inflammatory-related protein reflecting intestinal permeability pathology. Furthermore, zonulin showed a strong association with reduced quality of life. Although further detailed investigation is necessary, inflammatory cytokines and inflammatory-related proteins may be involved in the psychiatric symptoms of gluten intolerance.