UC San Diego researchers combined machine learning with molecular and animal studies to show that the immune sensor NOD2 pairs with the protein girdin (also known as GIV/CCDC88A) to keep intestinal inflammation in check; a common Crohn’s-associated frameshift in NOD2 disrupts this binding and tips macrophages toward pro-inflammatory states. The peer‑reviewed findings were published October 2, 2025, in the Journal of Clinical Investigation and validated in mouse colitis and sepsis models.
Crohn’s disease, a form of inflammatory bowel disease, involves a breakdown in the balance between inflammatory and reparative macrophages that help maintain intestinal health. When inflammatory macrophages predominate, chronic inflammation damages the intestinal wall and causes symptoms such as pain and diarrhea. (sciencedaily.com)
A team led by Pradipta Ghosh, M.D., professor of cellular and molecular medicine at UC San Diego School of Medicine, used AI to analyze thousands of macrophage gene-expression profiles from healthy and IBD-affected colon tissue. The approach identified a 53‑gene signature that consistently distinguishes inflammatory from restorative macrophages. (sciencedaily.com)
The work zeroed in on NOD2, the first gene linked to increased Crohn’s risk in 2001, and on girdin (GIV/CCDC88A), one of the 53 signature genes. In non‑inflammatory macrophages, NOD2 binds girdin to help sense bacteria, clear microbes, and maintain gut homeostasis. (sciencedaily.com)
Mechanistic experiments in the Journal of Clinical Investigation show that girdin’s C‑terminus binds the terminal leucine‑rich repeat (LRR#10) of NOD2. A Crohn’s‑associated frameshift variant in NOD2 (1007fs/3020insC) lacks this LRR#10 region and cannot bind girdin—impairing NOD2’s ability to dampen inflammation and clear microbes. (jci.org)
“NOD2 functions as the body’s infection surveillance system,” Ghosh said. “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.” (today.ucsd.edu)
To test the biology in vivo, the researchers used mouse models of colitis and sepsis in which girdin was depleted in myeloid cells. These models showed heightened gut inflammation, shifts in the microbiome, loss of NOD2’s protective effects, and increased mortality from sepsis. (dx.doi.org)
“The gut is a battlefield, and macrophages are the peacekeepers,” said co‑first author Gajanan D. Katkar, Ph.D., an assistant project scientist at UC San Diego School of Medicine. “For the first time, AI has allowed us to clearly define and track the players on two opposing teams.” (today.ucsd.edu)
By combining AI‑driven transcriptomics, biochemistry, and animal studies, the research addresses a long‑standing question about how NOD2 influences gut inflammation and points to potential treatments aimed at restoring the NOD2–girdin interaction. The study was published October 2, 2025, in the Journal of Clinical Investigation (DOI: 10.1172/JCI190851). (sciencedaily.com)