Background: Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals, resulting in villous atrophy, crypt hyperplasia, and mucosal inflammation. While immunologic mechanisms are well characterized, the role of mechanical and biochemical factors in disease onset remains underexplored.

Objective: To propose a novel dual-pathway hypothesis for CD pathogenesis that integrates mechanical compression from intraluminal pressure and biochemical disruption from nitrate-derived nitric oxide accumulation.

Methods: A conceptual model was developed through synthesis of published data on intestinal gas dynamics, microbial nitrate metabolism, nitric oxide signaling, and mucosal immunity. This hypothesis combines insights from gastrointestinal physiology and immunopathology to suggest new mechanistic pathways.

Results: Hypothesize that (1) excessive intraluminal gas exerts mechanical stress on villi, altering their structure and function; and (2) nitrate-derived nitric oxide disrupts epithelial motility and barrier integrity. These two mechanisms may act synergistically to enhance translocation of gliadin peptides and microbial antigens into the lamina propria, promoting inflammation and tissue injury.

Conclusion: This dual mechanism hypothesis offers a new perspective on CD by highlighting underrecognized non-immunologic contributors to disease progression. It may suggest novel therapeutic targets focused on intestinal gas modulation, microbial ecology, and nitrate handling.

Limitations: This hypothesis has not been tested experimentally due to current limitations in funding and research resources, which restrict in vivo and clinical validation.

Chronic functional abdominal pain, Crohn's disease, Crohn's disease, Gastroenterology, Gastrointestinal endoscopy, Inflammatory bowel disease