Colorectal laterally spreading tumors exhibit a distinct carcinogenic eco-metabolic shift defined by multi-omics...

Colorectal laterally spreading tumors (LSTs) are clinically important premalignant lesions with distinctive endoscopic morphology and malignant potential. Although microbiome and metabolome alterations have been reported in colorectal cancer and conventional adenomas, the microbial and metabolic features associated with LSTs remain insufficiently characterized.

We investigated whether LSTs are associated with a coordinated carcinogenic eco-metabolic shift (CES) involving stool microbial, metagenomic functional, and circulating metabolic alterations, hereafter referred to a CES, a finding consistent with its high-risk premalignant biology.

Building on our LST multi-omics cohort, we focused on stool metagenomic, serum metabolomic, and paired stool-serum datasets from 35 LST patients and 35 healthy controls. LST-associated microbial taxa, serum metabolites, and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional features were organized into CES modules according to their biological direction and functional themes. Cross-layer Spearman's analyses, functional pathway analyses, and sign-aligned CES scores were used to assess coordination across microbial, functional, and metabolic layers. Publicly available MetaGenoPolis stool metagenomic data were used as a reference cohort for comparisons across healthy controls, adenoma, and colorectal cancer (CRC) disease sequences.

LST patients showed a CES characterized by the depletion of protective anaerobe-associated taxa; enrichment of facultative/pathobiont-associated taxa; remodeling of dicarboxylate/TCA axis metabolism; alterations in amino acid and choline/glycerophospholipid metabolism; and enrichment of microbial functions related to carbohydrate uptake, central carbon metabolism, transport, and biofilm-associated adaptation. In paired stool-serum samples, four cross-layer associations were retained, including an exploratory inverse Roseburia-succinate relationship. In the MetaGenoPolis cohort, the matched microbial component of the CES showed a CRC-oriented pattern: CRC patients had higher microbial CES scores than healthy controls and adenoma patients, whereas the microbial CES scores of healthy controls and adenoma patients were not significantly different. Sign-aligned CES scores were higher in LST patients than in healthy controls across stool, serum, and paired multi-omics analyses; the paired integrated CES score showed a rank-biserial effect size of 0.952. A compact five-anchor CES representation, based on Roseburia depletion, succinate elevation, phosphotransferase system (PTS) elevation, 3-hydroxybutyric acid depletion, and Escherichia enrichment, preserved the main signal.

LSTs are associated with a coordinated CES involving stool microbial, microbial functional, and serum metabolic alterations. These findings support the CES as a testable framework for understanding high-risk premalignant colorectal biology and warrant validation in larger cohorts with adenoma and serrated lesion comparators.