Key findings: UC San Diego researchers used machine learning on gut immune cell gene-expression data to show that NOD2 mutations disrupt macrophage switching between inflammatory and repair states, driving intestinal inflammation in IBD. A 53-gene signature distinguishes protective versus harmful macrophage programs, and girdin partners with NOD2 to restrain excessive immune responses. Mouse models lacking girdin developed gut inflammation and often succumbed to sepsis, supporting the human-tissue results and suggesting new therapeutic targets.
How NOD2 Mutations Drive Crohn’s: Machine Learning Reveals a Macrophage Switch Failure
Key findings: UC San Diego researchers used machine learning on gut immune cell gene-expression data to show that NOD2 mutations disrupt macrophage switching between inflammatory and repair states, driving intestinal inflammation in IBD. A 53-gene signature distinguishes protective versus harmful macrophage programs, and girdin partners with NOD2 to restrain excessive immune responses. Mouse models lacking girdin developed gut inflammation and often succumbed to sepsis, supporting the human-tissue results and suggesting new therapeutic targets.
08:24 PM, 11/16/2025Health
Researchers uncover how NOD2 mutations tip gut immune cells toward damaging inflammation
Scientists at the University of California, San Diego have identified a key mechanism by which variants of the NOD2 gene—previously linked to Crohn’s disease—promote intestinal inflammation. Using machine learning to analyze gene-expression patterns in gut immune cells, the team traced how these mutations prevent macrophages from switching between repair and attack modes, causing an immune imbalance that can damage the gut.
Machine learning reveals macrophage programs
The researchers applied machine-learning techniques to gene-expression data from intestinal immune cells and derived a 53-gene signature that distinguishes protective, repair-oriented macrophages from inflammatory, tissue-damaging ones. By following these signatures in cultured cells and patient tissue samples, they mapped which cell programs support gut health and which drive disease.
"The gut is a battlefield, and macrophages are the peacekeepers," said Gajanan Katkar of UC San Diego. "For the first time, AI has allowed us to clearly define and track the players on two opposing teams."
Girdin and NOD2: a critical partnership
One of the genes linked to the non-inflammatory, repair state encodes a protein called girdin. The study shows that girdin and NOD2 physically and functionally cooperate: together they help macrophages detect and neutralize pathogens efficiently while avoiding excessive inflammation. When this partnership breaks down—either because of NOD2 variants or loss of girdin—repair-mode macrophages fail to clear debris effectively and attack-mode macrophages become hyperinflammatory.
"NOD2 functions as the body's infection surveillance system," said cell biologist Pradipta Ghosh. "When bound to girdin, it detects invading pathogens and maintains gut immune balance by swiftly neutralizing them. Without this partnership, the NOD2 surveillance system collapses."
Mouse models and clinical implications
Mouse experiments supported the cellular and tissue findings: animals lacking girdin developed intestinal inflammation and many progressed to sepsis and death, consistent with an uncontrolled immune response. These results clarify how NOD2 variants can contribute specifically to Crohn’s disease amid other genetic and environmental risk factors.
While the study advances understanding of macrophage imbalance in IBD, it remains preclinical. The authors note that identifying the NOD2–girdin axis and the 53-gene signature opens potential therapeutic avenues, such as drugs that restore the macrophage switch or mimic girdin–NOD2 function to rebalance gut immunity.
Publication: The study was published in the Journal of Clinical Investigation.
Takeaway
By combining machine learning with cellular and animal experiments, this work connects NOD2 genetic variants to a specific failure in macrophage state switching—offering a clearer molecular explanation for how those variants raise Crohn’s risk and pointing to new, targeted strategies for therapy.