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, an ulcerative colitis-like (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 developed severe colitis and, notably, spontaneous CAC that progressively worsened over time. In contrast, CONV Winnie mice showed only mild colitis but no tumorigenesis. By comparison, when re-derived 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 proinflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Using either SPF Winnie or WT (Bl/6) donors, fecal microbiota transplantation (FMT) into GF Winnie recipients demonstrated that, while colitis developed regardless of the donor, only FM from SPF Winnie donors resulted in CAC in recipient mice. Our studies present a relevant model of CAC, providing strong evidence that the microbiome plays a key role in its pathogenesis, thus challenging the concept of colon cancer as a strictly nontransmissible disease.