Immunopathophysiology of Gluten-Associated Insulin Resistance: A 33-mer Gliadin–CXCR3–Zonulin Axis Driving IRAK4-Centered Innate Immune Amplification, Sulfur Depletion, and Upstream Modulation by <em>Aspergillus niger </em>Prolyl Endopeptidase

Insulin resistance is increasingly recognized as a disorder of immunometabolic integration rather than a purely metabolic defect. Although chronic low-grade inflammation is known to impair insulin signaling, the upstream dietary and mucosal drivers sustaining innate immune activation in susceptible individuals remain incompletely defined. Here, we propose an immunopathophysiological hypothesis linking digestion-resistant gliadin peptides particularly the canonical 33-mer fragment to systemic insulin resistance through a gut-initiated innate immune cascade coupled to sulfur and redox dysregulation. The 33-mer gliadin peptide resists gastrointestinal proteolysis, permitting prolonged luminal persistence and sustained epithelial interaction. Experimental evidence demonstrates that gliadin binds the epithelial chemokine receptor CXCR3, inducing zonulin release and transient modulation of tight junctions. This regulated increase in intestinal permeability facilitates enhanced mucosal access of dietary peptides and microbial ligands to innate immune cells. We propose that this co-exposure potentiates MyD88-dependent Toll-like receptor signaling, with IRAK4 functioning as a central signaling hub. IRAK4-driven activation of NF-κB and stress kinase pathways interferes with insulin signaling while simultaneously imposing a chronic oxidative and nitrosative burden. Sustained innate immune activation accelerates glutathione consumption and suppresses transsulfuration pathway capacity, resulting in functional sulfur depletion. This redox imbalance compromises protein disulfide isomerase activity and insulin disulfide bond formation, linking mucosal immune activation to impaired insulin structural integrity, reduced bioactivity, hyperinsulinemia, and systemic insulin resistance. As an upstream experimental intervention, Aspergillus niger–derived prolyl endopeptidase is proposed to degrade resistant gliadin peptides prior to epithelial engagement and innate immune amplification. This falsifiable framework supports biomarker-guided stratification and staged validation across luminal peptide degradation, epithelial barrier modulation, innate immune signaling, sulfur metabolism, and tissue-level insulin responsiveness.