A joint team led by Dr. Jingnan Li and Dr. Ji Li of Peking Union Medical College Hospital, along with Associate Professor Xiaohuan Guo of Tsinghua University and Scholar Ye-Guang Chen of Tsinghua University School of Life Sciences, published the research in the journal Volume 2, Article No. 28. immunity and inflammation Researchers integrated single-cell RNA sequencing, spatial transcriptomics, and functional experiments to uncover the molecular mechanisms underlying colonic lesion formation in Cronkheit-Canada syndrome (CCS).
CCS is an extremely rare non-hereditary hamartomatous polyposis syndrome characterized by diffuse gastrointestinal polyposis and characteristic ectodermal changes such as alopecia, onychodystrophy, skin hyperpigmentation, and often diarrhea, malabsorption, and weight loss. Since it was first reported in 1955, the pathogenesis of CCS has remained a mystery. Unlike hereditary hamartomatous polyposis syndromes such as Peutz-Jeghers syndrome and juvenile polyposis syndrome, CCS has no discernible germline pathogenic mutations. Although previous clinical observations have suggested an autoimmune role, the specific characteristics of immune dysregulation and the precise cellular and molecular mechanisms driving colon hamartoma formation have remained unclear for decades.
To address this gap, the research team first performed single-cell transcriptome analysis on colon biopsy samples from CCS patients and healthy controls. They found extensive epithelial remodeling in CCS patients compared to healthy individuals. Goblet cells were significantly proliferated and had dramatically elevated transcript levels of multiple mucin genes, including: MUC2, MUC4, MUC5ACand MUC5B. Additionally, CCS samples had a significantly increased inflammatory colonic epithelial cell subset characterized by high expression of lipocalin 2 (LCN2). These findings indicate that the colonic epithelium in CCS undergoes profound secretory and inflammatory reprogramming.
What is causing this anomaly? Clues indicating the immune microenvironment were obtained. In the intestines of CCS patients, TNF-α producing CD4+ T cells were significantly expanded compared to healthy controls. On the other hand, macrophages secreting IL-1β showed an abnormal spatial distribution and colocalized with hyperplastic colonic goblet cells. Intercellular communication analysis based on ligand-receptor interaction inference, in vitro Co-culture experiments revealed a potential pathogenic cascade. TNF-α released from CD4+ T cells promoted the conversion of monocytes into IL-1β-secreting macrophages. IL-1β then directly stimulated intestinal epithelial cells to secrete mucus, while simultaneously inducing the production of prostaglandin E2 (PGE2) by the epithelium. PGE2 further promoted IL-1β production in macrophages, establishing a self-amplifying positive feedback loop. This TNF-α/IL-1β/PGE2 axis is thought to promote persistent mucus hypersecretion, epithelial remodeling, and ultimately hamartomatous polyp formation in CCS.
To validate their findings, the team studied an independent cohort of CCS patients. Patients with active CCS had significantly elevated serum TNF-α levels compared to healthy controls. Immunohistochemistry and histochemical staining of colonic biopsy samples confirmed aberrant mucin secretion and activation of inflammatory pathways, consistent with single-cell sequence predictions. Patients in clinical remission showed decreased TNF-α levels and less pronounced mucin abnormalities, further supporting the clinical relevance of the proposed mechanism.
In summary, this study provides the first multiomic picture of colonic lesions in CCS and provides new insights into the pathogenesis of this rare and poorly understood disease. ”The identification of the TNF-α/IL-1β/PGE2 axis as a driver of mucus accumulation and hamartoma formation provides a theoretical basis for treating refractory CCS with existing biologics such as anti-TNF-α antibodies (e.g., infliximab) or anti-IL-1 agents (e.g., anakinra).” concludes the author.Future clinical trials are needed to evaluate the efficacy of such targeted immunotherapies in patients with CCS.”
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Reference magazines:
Zhi, Y. Others. (2026). Multi-omics reveals colonic lesion formation via mucus accumulation by TNF-α/IL-1β/PGE2 axis in Cronkheit-Canada syndrome. immunity and inflammation. DOI: 10.1007/s44466-026-00045-1. https://link.springer.com/article/10.1007/s44466-026-00045-1
