The gut microbiome can contribute to colon tumor susceptibility via an effect on CD8+ T cell responses

Abstract

Abstract There is increasing evidence that colorectal cancer patients have altered gut microbiomes compared to healthy controls, but the mechanisms by which the microbiota contribute to colon carcinogenesis remain to be fully elucidated. Using the azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model of inflammation-associated colon tumorigenesis, our lab discovered two colonies of specific pathogen free (SPF) C57BL/6J wild type (WT) mice housed in the same mouse room that develop differential tumor burdens. Mice from the “WT1” colony developed five tumors on average while mice from the “WT2” colony developed 15 tumors on average. The increased tumor susceptibility in WT2 mice can be directly attributed to the gut microbiome as germ-free (GF) mice colonized with WT2 bacteria developed more tumors compared to that of GF mice colonized with WT1 bacteria. Additionally, 16S rRNA gene sequencing of fecal bacteria from WT1 and WT2 mice revealed distinct microbiomes with certain bacteria consistently associated with high or low tumor numbers. Furthermore, naïve and acutely-inflamed (day 10 of AOM/DSS) WT2 mice have increased colon lamina propria CD8+ IFNγ+ T cells compared to WT1 mice as measured by flow cytometry. However, in tumor-bearing WT2 mice, there was decreased tumor-infiltrating CD8+ T cells with reduced IFNγ production, possibly due to T cell exhaustion. GF Rag1−/− mice as well as SPF CD8−/− mice inoculated with WT2 gut microbiota developed fewer tumors than SPF WT2 mice, suggesting that the WT2 gut microbiome increases tumor susceptibility, in part, through an effect on CD8+ T cells. Altogether, our data reveal a potential novel role of microbiota in altering colon CD8+ T cell function that ultimately impacts colon cancer risk.