Scientists uncover immune mechanisms driving rare gastrointestinal disorder

A collaborative team led by Dr. Jingnan Li and Dr. Ji Li at Peking Union Medical College Hospital, together with Associate Professor Xiaohuan Guo at Tsinghua University and Academician Ye-Guang Chen at Tsinghua University School of Life Sciences, published a study in Volume 2, article number 28 of the journal Immunity & Inflammation on June 17, 2026. The researchers integrated single-cell RNA sequencing, spatial transcriptomics, and functional experiments to uncover the molecular mechanisms underlying colonic lesion formation in Cronkhite-Canada syndrome (CCS).

CCS is an extremely rare, non-hereditary hamartomatous polyposis syndrome characterized by diffuse gastrointestinal polyposis and distinctive ectodermal changes including alopecia, nail dystrophy, skin hyperpigmentation, and often diarrhea, malabsorption, and weight loss. Since its first description in 1955, the etiology of CCS has remained enigmatic. Unlike hereditary hamartomatous polyposis syndromes such as Peutz–Jeghers syndrome or juvenile polyposis syndrome, CCS lacks identifiable germline pathogenic mutations. Previous clinical observations have suggested autoimmune involvement, but the specific immune dysregulation features and the precise cellular and molecular mechanisms driving colonic hamartoma formation have remained unclear for decades.

To address this gap, the research team first performed single-cell transcriptomic analysis on colonic biopsy samples from CCS patients and healthy controls. They discovered extensive epithelial remodeling in CCS patients compared to healthy individuals. Goblet cells were markedly hyperplastic, with dramatically elevated transcript levels of multiple mucin genes, including MUC2, MUC4, MUC5AC, and MUC5B. In addition, an inflammatory colonic epithelial cell subset characterized by high expression of lipocalin-2 (LCN2) was significantly increased in CCS samples. These findings indicate that the colonic epithelium in CCS undergoes a profound secretory and inflammatory reprogramming.

What drives this abnormality? Clues pointed to the immune microenvironment. In the intestines of CCS patients, TNF-α-producing CD4⁺ T cells were significantly expanded compared to healthy controls. Meanwhile, IL-1β-secreting macrophages showed aberrant spatial distribution, co-localizing with hyperplastic colonic goblet cells. Cell–cell communication analysis based on ligand–receptor interaction inference, combined with 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 and simultaneously induced epithelial production of prostaglandin E₂ (PGE₂). PGE₂ further promoted IL-1β production in macrophages, establishing a self-amplifying positive feedback loop. This TNF-α/IL-1β/PGE₂ axis appears to drive persistent mucus hypersecretion, epithelial remodeling, and ultimately the formation of hamartomatous polyps in CCS.

To validate their findings, the team examined an independent cohort of CCS patients. Active CCS patients showed significantly elevated serum TNF-α levels compared to healthy controls. Immunohistochemistry and histochemical staining of colonic biopsy samples confirmed abnormal mucin secretion and activation of inflammatory pathways consistent with the single-cell sequencing predictions. Patients in clinical remission showed reduced TNF-α levels and less pronounced mucin abnormalities, further supporting the clinical relevance of the proposed mechanism.

In summary, this study provides the first multi-omics landscape of colonic lesions in CCS, offering 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)," the authors conclude. "Future clinical trials are needed to evaluate the efficacy of such targeted immunotherapies in CCS patients."