A groundbreaking study co-led by Shehzad Z. Sheikh, MD, PhD, professor of medicine in the UNC Division of Gastroenterology and Hepatology, and Matthew N. Poy, PhD, associate professor of medicine with Johns Hopkins University, reveals Cell Adhesion Molecule 1 (CADM1), a surface protein involved in cell-cell adhesion, is significantly elevated in the intestinal tissues of IBD patients. The research also shows CADM1 may fuel ongoing immune activation.
The findings, published in Cellular and Molecular Gastroenterology and Hepatology, suggest CADM1 could serve both as a biomarker for disease severity and a potential therapeutic target to reduce inflammation in conditions such as Crohn’s disease and ulcerative colitis.
“Our data show that CADM1 is enriched in myeloid immune cells in the gut and acts as a bridge to activate CD8+ cytotoxic T cells,” said Dr. Sheikh. “These T cells can damage the intestinal lining, so preventing their activation could reduce disease severity.”
Evidence from Human and Mouse Models
The study combined several cutting-edge technologies, including RNA sequencing, single-cell transcriptomics, spatial proteomics, and in vivo mouse models. The researchers found CADM1 expression was significantly upregulated in the inflamed colons of IBD patients compared to non-IBD controls. Notably, CADM1+ myeloid cells were located adjacent to CD8+ T cells in patient samples, implying a direct role in T cell activation.
To test this mechanism, the team engineered mice with myeloid-specific deletion of Cadm1 and exposed them to DSS, a chemical that induces colitis. These mice showed markedly less intestinal inflammation, fewer activated T cells, and better preservation of intestinal tissue compared to controls. Moreover, treatment with a CADM1-blocking antibody also reduced disease severity in a separate colitis model, providing proof-of-concept for therapeutic intervention. These results strongly suggest that CADM1 plays a role in promoting intestinal inflammation. Blocking it could reduce disease severity, offering a potential path for developing new treatments.
CADM1 as a Circulating Biomarker
Beyond the gut, the study found elevated levels of soluble CADM1 (sCADM1) in the blood of patients with both ulcerative colitis and Crohn’s disease, particularly in those with severe or surgery requiring disease. Recombinant sCADM1 was shown to activate pro-inflammatory STAT3 signaling in human immune cells, further implicating its role in systemic inflammation.
“This sheds light on a previously underappreciated molecule in IBD pathogenesis,” said Dr. Sheikh. “sCADM1 might serve as a blood-based biomarker to identify patients with active disease or predict who is at risk of flares.”
CADM1 has also been implicated in other chronic inflammatory conditions, including type 1 diabetes and chronic kidney disease. This suggests it may be part of a broader inflammatory network.
Future Directions
The discovery of CADM1’s role in IBD has significant therapeutic implications. Most current biologics target cytokines or lymphocyte trafficking. CADM1 represents a new class of target an adhesion molecule that orchestrates cell-cell interactions at the epithelial-immune interface.
Because CADM1 expression is elevated specifically in immune cells during active disease and because blocking its function appears to reduce inflammation, researchers are optimistic about future clinical translation,” Dr. Sheikh said. “We envision CADM1 inhibition as a novel therapeutic strategy, especially for patients who are refractory to current therapies.”
This work was supported by numerous NIH grants, the Helmsley Charitable Trust, the Crohn’s and Colitis Foundation, and Morphic Therapeutics. Read more about Dr. Sheikhs’ lab here.