Abstract
Gut microbiota dysbiosis is strongly linked to colorectal cancer (CRC), but reliable early diagnostic markers remain elusive. This study investigates the role of a novel Shigella flexneri strain in CRC pathogenesis. Metabolomic analysis of CRC patient feces identified elevated agmatine levels. A unique agmatine-producing strain (S. flexneri C.11) was isolated and validated in cell models and pseudo-sterile mice. Affinity fishing combined with HPLC-QTOF-MS characterized bacterial metabolites, while RNA sequencing elucidated mechanistic pathways. Repeated S. flexneri C.11 exposure-induced DNA damage and inflammatory-to-neoplastic transformation. Three genotoxic cyclodipeptides (CDP1-3) were identified, driving malignant transformation and accelerating colitis-associated tumorigenesis. Mechanistically, S. flexneri C.11 upregulated ERBB3, activating the PI3K-AKT pathway. Clinically, combined detection of S. flexneri C.11 and its metabolites differentiated CRC patients from healthy controls (AUC = 0.887), suggesting its potential as noninvasive diagnostic biomarkers for CRC. We identify S. flexneri C.11 as a pro-carcinogenic pathogen and propose ERBB3/PI3K - AKT signaling as a therapeutic target.