Rebalancing the Gut: How AI Solved a 25-Year Crohn’s Disease Mystery

Electron micrographs show how macrophages expressing girdin neutralize pathogens by fusing phagosomes (P) with the cell’s lysosomes (L) to form phagolysosomes (PL), compartments where pathogens and cellular debris are broken down (left). This process is crucial for maintaining cellular homeostasis. In the absence of girdin, this fusion fails, allowing pathogens to evade degradation and escape neutralization (right).
Image Credit: UC San Diego Health Sciences

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. 

Researchers at University of California San Diego School of Medicine 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 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.

Co-first author Mahitha Shree Anandachar (center), a Ph.D. student in Biomedical Sciences at UC San Diego, with student research assistant Jasmin Salem (left) and Pradipta Ghosh, M.D. (right).
Photo Credit: UC San Diego Health Sciences

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.

“NOD2 functions as the body’s infection surveillance system,” said senior author Pradipta Ghosh, M.D., professor of cellular and molecular medicine at UC San Diego School of Medicine. “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.”

Co-first author Mahitha Shree Anandachar (center), a Ph.D. student in Biomedical Sciences at UC San Diego, with student research assistant Jasmin Salem (left) and Pradipta Ghosh, M.D. (right). (UC San Diego Health Sciences)

The researchers then confirmed the importance of the interaction between NOD2 and girdin by comparing mouse models of Crohn’s disease lacking the girdin protein to those with girdin intact. They found that mice without girdin suffered an imbalance in their gut microbiome and developed inflammation of the small intestine. They often died of sepsis, a condition in which the immune system mounts an excessive response to an infection, causing inflammation throughout the body and damage to vital organs.

“The gut is a battlefield, and macrophages are the peacekeepers,” said co-first author Gajanan D. Katkar, Ph.D., 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.”

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.

Published in journal: Journal of Clinical Investigation

Title: Distinct colitis-associated macrophages drive NOD2-dependent bacterial sensing and gut homeostasis

Authors: Gajanan D. Katkar, Mahitha Shree Anandachar, Stella-Rita C. Ibeawuchi, Ella G. McLaren, Megan L. Estanol, Kennith Carpio-Perkins, Shu-Ting Hsu, Celia R. Espinoza, Jane E. Coates, Yashaswat S. Malhotra, Madhubanti Mullick, Vanessa Castillo, Daniella Vo, Saptarshi Sinha, and Pradipta Ghosh

Source/Credit: University of California San Diego | Susanne Clara Bard 

Reference Number: mcb102725_01

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