Coeliac barrier review 2026 — B-Gen-2 mechanism-loading anchor (H5/H5b cure-path arm)

One-paragraph summary

Review of intestinal barrier dysfunction as central to coeliac disease pathophysiology in HLA-DQ2/DQ8-genetically-predisposed individuals exposed to dietary gluten. Reviews evidence and mechanisms: zonulin signaling, inflammatory cytokines, microbial alterations, immune responses to gliadin peptides. Comprehensively reviews therapies targeting barrier integrity: dietary supplements, larazotide acetate (zonulin antagonist), IMU-856 (an investigational barrier-restoring agent), and other experimental therapies. Highlights need for reliable biomarkers for evaluating intestinal permeability in coeliac and advocates further barrier-function-normalizing research as a remission-maintenance strategy. Strongest single mechanism-loading anchor for B-Gen-2 (celiac-spectrum disease ↔ FM via shared genetic substrate) and for the larazotide cure-path arm in both H5 and H5b. Adds IMU-856 as a second candidate barrier-restoring compound class.

Claims as triples

• HLA_DQ2_DQ8 — required_for → celiac_spectrum_disease [evidence: established celiac genetics; confidence: established]
• gluten — drives → intestinal_permeability [evidence: review in celiac; confidence: established]
• zonulin — modulates → tight_junction_complex [evidence: review; confidence: established]
• larazotide_acetate — restores → tight_junction_complex [evidence: review of clinical trial data; confidence: emerging]
• IMU_856 — restores → tight_junction_complex [evidence: review of preclinical/early-clinical; confidence: emerging]
• celiac_spectrum_disease — drives → intestinal_permeability [evidence: established mechanism; confidence: established]

Methods note

Comprehensive narrative review of celiac-disease barrier-mechanism literature spanning ~20 years. Synthesizes zonulin pathway, gliadin-peptide immune-recognition, microbial contribution. Therapeutic section catalogs barrier-restorative agents at all development stages — supplements through clinical-trial-stage compounds.

Limitations

• Narrative, not systematic
• Celiac-focused; FM extension is project-driven (not paper-driven)
• IMU-856 development stage and mechanism details limited
• Biomarker validation for barrier function still incomplete

Open questions raised

• Q-IBC-16 (new): Is IMU-856 a candidate H5b cure-path-arm alongside larazotide acetate? Two different barrier-restoring compound classes for the MYO9B/OCLN/TJP1/CLDN2-stratified subgroup. Investigational stage — track for clinical readouts.
• Q-IBC-17 (new): Are zonulin levels in FM-IgG-positive patients correlated with anti-SGC IgG titer? The Dorta-Aguilar 2023 anchor measured zonulin in FM/ME-CFS but did not stratify on anti-SGC IgG status. Cross-stratification within the existing project cohort biobank would test directly.

Triangulation notes

• B-Gen-2 mechanism-loading anchor: this review supplies the strongest single-source mechanism narrative the celiac-spectrum bridge has. Zonulin → tight-junction → barrier failure → systemic immune activation is the canonical mechanism, now cited in the project at review tier.
• Larazotide acetate cure-path arm: this review confirms larazotide is in active clinical development with Phase 2/3 celiac readouts. Adds IMU-856 as second-line candidate.
• Compatible with Dorta-Aguilar 2023 + Jakobsson 2026: those papers documented intestinal permeability + bile-acid translocation in FM patients; this review supplies the mechanism that generates the permeability (zonulin-driven tight-junction failure in HLA-DQ2/DQ8 + gluten background).
• Connects to H5/H5b multi-layer barrier-failure framework: zonulin operates on tight-junction proteins (which include OCLN and TJP1 in the H5b module + CLDN2 in the H5 module). Multi-genetic-vulnerability in those layers would amplify zonulin-driven barrier failure per unit gluten exposure.

Bridges

• B-Gen-2 mechanism-loading: bridge gains its primary mechanism-source anchor. Status remains bridging because FM-direct closure still requires cohort-level FM-celiac comorbidity prevalence + anti-tTG seroprevalence (Q-Gen-3) + HLA-DQ2/DQ8 carriage (Q-Gen-1) tests.
• B-Gen-3 + H5b larazotide arm: this review confirms larazotide is candidate FM-repurposing-tractable. The H5b cure-path arm at the barrier-failure layer is anchored on a clinical-stage compound.

Ontology additions needed

• Add zonulin to relationships (entity may already exist from Dorta-Aguilar 2023 anchor — verify)
• Add IMU_856 as new intervention entity
• Confirm larazotide_acetate entity description includes Phase 3 celiac development stage

Chain-map update

• H5/H5b barrier-failure layer: now anchored on the canonical celiac-zonulin mechanism. The H5 + H5b cure-path arm at "tight-junction restoration" includes both larazotide acetate (in clinical development) and IMU-856 (investigational).
• B-Gen-2 framing: the celiac mechanism narrative is now cited at review tier within the project, providing the conceptual foundation for the FM-direct stratification studies (Q-Gen-1, Q-Gen-3, Q-IBC-4).

Confidence-tier framing

• Zonulin-mediated tight-junction disruption in celiac: established (decades of canonical evidence)
• Larazotide acetate as barrier-restoring agent in celiac: emerging (Phase 2/3 data)
• IMU-856 as second-generation barrier agent: emerging (investigational stage)
• Same mechanism operative in FM: bridging (project-driven extrapolation)
• B-Gen-2 mechanism-loading: emerging (review-tier consolidation)