On Oct. 27, 2025, researchers at University of California San Diego School of Medicine (UC San Diego) have settled a decades-long debate surrounding the role of the first Crohn’s disease gene to be associated with a heightened risk for developing the auto-immune condition.

Researchers at UC San Diego have developed a new approach that integrates artificial intelligence (AI) with advanced molecular biology techniques to decode what determines whether a macrophage will become inflammatory or non-inflammatory.

The human gut contains two types of macrophages, or specialized white blood cells, that have very different but equally important roles in maintaining balance in the digestive system. Inflammatory macrophages fight microbial infections, while non-inflammatory macrophages repair damaged tissue. In Crohn’s disease — a form of inflammatory bowel disease (IBD) — an imbalance between these two types of macrophages can result in chronic gut inflammation, damaging the intestinal wall and causing pain and other symptoms.

The study also resolves a longstanding mystery surrounding the role of a gene called NOD2 in this decision-making process. NOD2 was discovered in 2001 and is the first gene linked to a heightened risk for Crohn’s disease.

Using a powerful machine learning tool, the researchers analyzed thousands of macrophage gene expression patterns from colon tissue affected by IBD and from healthy colon tissue. They identified a macrophage gene signature consisting of 53 genes that reliably separates reactive, inflammatory macrophages from tissue-healing macrophages.

One of these 53 genes encodes a protein called girdin. Further analysis revealed that in non-inflammatory macrophages, a specific region of the NOD2 protein binds to girdin. This suppresses runaway inflammation, clears harmful microbes and allows for the repair of tissues damaged by IBD. But the most common Crohn’s disease mutation to the NOD2 gene deletes the section of the gene that girdin would normally bind to. This results in a dangerous imbalance between inflammatory and non-inflammatory macrophages.

By uniting AI-driven classification, mechanistic biochemistry, and mouse models, the study resolves one of the longest-running debates in Crohn’s disease. The findings not only explain how a key genetic mutation drives the disease but could also contribute to the development of treatments aimed at restoring the relationship between girdin and NOD2. The study was published in the Journal of Clinical Investigation.