A missense mutation in Muc2 promotes gut microbiome and metabolome-dependent colitis-associated tumorigenesis.

Colitis-associated cancer (CAC) arises from a complex interplay between host and environmental factors. In this report, we investigated the role of the gut microbiome using Winnie mice, a UC-like model with a missense mutation in the Muc2 gene. Upon rederivation from a conventional (CONV) to a specific-pathogen-free (SPF) facility, Winnie mice exhibited severe colitis and, notably, spontaneous CAC, progressively worsening over time. In contrast, CONV Winnie showed only mild colitis but no tumorigenesis. Notably, when rederived into germ-free (GF) conditions, SPF Winnie mice were protected from colitis and colon tumors, indicating an essential role for the gut microbiome in the development of CAC in these mice. Using shotgun metagenomics, metabolomics, and lipidomics, we identified a distinct pro-inflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Fecal microbiota transplantation (FMT), using either SPF Winnie or WT (Bl/6) donors into GF Winnie recipients, demonstrated that while colitis developed regardless of the donor, only FMT from SPF Winnie donors resulted in CAC. Our studies present a novel and relevant model of CAC, providing strong evidence that microbiome plays a key role in the pathogenesis of CAC, thereby challenging the concept of colon cancer as a strictly non-transmissible disease.