Deciphering immune and cellular reprogramming during the progression from inflammatory bowel disease to colorectal cancer using multi-omics single-cell and spatial transcriptomics.

BACKGROUND: Inflammatory bowel disease (IBD) represents a group of chronic and relapsing inflammatory disorders of the gastrointestinal tract, primarily encompassing Crohn’s disease (CD) and ulcerative colitis (UC). To elucidate immune heterogeneity and molecular mechanisms underlying IBD pathogenesis, we performed an integrated high-resolution transcriptomic and experimental analysis across 1436 patients with IBD and CRC. METHODS: 436 samples in transcriptomics level were analyzed, including 415 bulk RNA-seq, 18 single-cell RNA-seq (10x Genomics), and 3 spatial transcriptomic (Visium) samples from human intestinal tissue. Additionally, serum carcinoembryonic antigen (CEA) levels were evaluated in 1000 patients diagnosed with IBD (CD or UC) and colorectal cancer (CRC). RESULTS: Single-cell analysis identified major immune and stromal cell types, among which epithelial cells, T cells, B cells, and tissue stem cells were the most abundant in both CD and UC tissues. Comparative profiling revealed an increase in epithelial and stem cell populations in diseased tissues, indicating enhanced epithelial regeneration and immune activation. Integration of bulk and single-cell RNA-seq datasets highlighted several disease-associated genes, including: CEACAM5, LGALS1, NUAK1, and PDGFRA, with CEACAM5 showing consistent upregulation across CD and UC samples. Pseudotime trajectory analysis demonstrated that CEACAM5 expression increased during the later stages of epithelial cell differentiation and suggesting its involvement in mucosal remodeling and chronic inflammation. Spatial transcriptomic mapping confirmed localized CEACAM5 overexpression in epithelial regions of colorectal cancer tissues, further supporting its role in disease progression. Serological analysis revealed that serum CEA levels were significantly higher in CRC compared to IBD and within IBD, Crohn’s disease patients exhibited higher CEA levels than ulcerative colitis patients (P < 0.05). CONCLUSIONS: Collectively, these findings indicate that CEACAM5 (CEA) serves as a key molecular marker linking epithelial activation in IBD to tumorigenic processes in colorectal cancer and providing potential diagnostic and prognostic value for distinguishing inflammatory bowel disease and colorectal cancer.