A Minimal Causal Model of Crohn's Disease: Re-ordering the Core Genetic and Immunological Axes Toward a Curative Framework

Crohn’s disease is highly polygenic, with approximately 200 associated loci identified by genome-wide association studies, yet only a small number of biological pathways have yielded effective therapies. This disparity suggests that most genetic associations reflect downstream modifiers rather than independent causal origins of disease.

Here, I propose that Crohn’s disease can be explained by a minimal causal module composed of five interacting biological nodes: NOD2 (microbial sensing), ATG16L1/IRGM (autophagy and Paneth cell function), XBP1 (epithelial endoplasmic reticulum stress), IL23R (IL-23/Th17 immune amplification), and MUC2 (mucus barrier integrity). I argue that disruption of this compact circuit is sufficient to generate the canonical features of ileal Crohn’s disease, including Paneth cell dysfunction, dysbiosis, chronic Th17 inflammation, and fibrostenosing complications, with the remaining genetic loci acting primarily as context-dependent modifiers or amplifiers.

Reframing Crohn’s disease in terms of a causal hierarchy rather than diffuse polygenicity resolves several paradoxes in genetics, pathology, and therapeutic response. It also shifts the definition of cure from indefinite immunosuppression toward upstream restoration of damaged circuit components. I outline falsifiable predictions arising from this model and propose a rational path toward durable remission or cure through node-specific intervention, including precise genetic repair.

This work is intended to challenge the prevailing status quo in inflammatory bowel disease research by explicitly prioritizing causal depth over associative breadth.