From Bile Dysmetabolism to Lipid-Metabolic Remodeling of the Distal Colon: A Vectorial Concept of Colorectal Carcinogenesis (Part I).

Colorectal cancer (CRC) is traditionally viewed as the result of the sequential accumulation of molecular alterations and the clonal expansion of transformed cells. However, the state of morphologically non-neoplastic mucosa preceding the development of neoplasia remains considerably less well characterized. This narrative review aims to integrate evidence on biliary and lipid metabolism, intestinal transit, microbial metabolism, and field cancerization and to formulate a testable model of early metabolic remodeling in the distal colon. We propose that a chronically altered biliary-metabolic environment, combined with prolonged luminal and mucosa-associated exposure, may promote lipid-metabolic remodeling of morphologically non-neoplastic mucosa. This state is considered not as a new disease entity but as a potential tissue phenotype capable of altering the barrier, metabolic, and regenerative properties of the epithelium. Subsequent exposure to nitrogen-containing products of microbial metabolism may sustain repeated cycles of injury and regeneration, thereby creating conditions for clonal selection. Following the emergence of a neoplastic clone, the same local environment may potentially assume a different biological role and become part of a metabolic niche that supports further clonal expansion. The proposed model extends the concept of field cancerization by incorporating a metabolic dimension and generates a series of spatial and temporal predictions amenable to experimental and prospective clinical testing. Validation of this model may provide a basis for investigating morphologically non-neoplastic mucosa as potential tissue at risk and for developing earlier preventive and diagnostic approaches.