Microbial metabolite trimethylamine-N-oxide facilitates colorectal inflammation-cancer transformation by blocking lysosomal degradation of Wnt signaling

Chronic inflammation is closely related to the occurrence and development of many tumors, including colorectal cancer (CRC), a typical inflammation-dependent cancer. The gut bacteria and their metabolites, as signaling molecules or substrates of metabolic processes, have attracted increasing attention during the colorectal inflammation-cancer transformation process. However, how commensal microbiota-derived metabolites create a favorable internal environment for carcinogenesis through the chronic inflammatory response is not entirely understood. Here, we conducted multiomics analysis, including single-cell RNA-sequencing (scRNA-seq), microbiome and metabolome to explore the intricate cross-talk of host-microbe-metabolite. By employing colitis-associated CRC mice models, as well as patient-derived CRC organoids, we identified that trimethylamine n-oxide (TMAO), a metabolic product derived from the gut microbiota, was crucial for inflammation-mediated colorectal carcinogenesis by enhancing Wnt signaling. Further mechanistic studies revealed that TMAO interacted with heat shock protein family A member 8 (Hspa8, also known as Hsc70), a molecular chaperone that mediates autophagy, to block the lysosomal degradation of the β-catenin protein, leading to an increase in the downstream targets cyclin D1 and c-Myc, thus contributing to colorectal carcinogenesis. Our results indicated that TMAO serves as a bridge to establish the connection between microbiota and colorectal carcinogenesis, playing a critical pathogenic role during CRC progression and therefore provides novel mechanistic insights into the intestinal inflammation in colorectal neoplasia progression.