Abstract 4076: Gut microbiota and metabolite-driven phenotype modulation in a mouse model of colorectal cancer

Colorectal cancer (CRC) is a multifactorial disease that develops as a result of multiple genetic mutations, often including loss of the tumor suppressor Adenomatous Polyposis Coli (APC) gene. More recently, additional factors such as the host gut microbiota (GM) have also demonstrated an important role in tumor initiation and progression, yet our understanding of most commensal bacteria remains limited. We observed significant differences in intestinal tumor multiplicity between two ApcMin sub-strain mouse colonies; C57BL/6J-ApcMin (B6-Min/J) mice from The Jackson Laboratory had relatively lower adenoma burden while C57BL/6JD-ApcMin (B6-Min/D) mice from the University of Wisconsin develop twice the number of adenomas. To determine the underlying causes of this phenotypic variability, we used complex microbiota targeted rederivation (CMTR) to rederive embryos of the two Apc mutant sub-strains onto surrogate dams harboring distinct GM from two different vendors (GMJAX and GMHSD), generating four ApcMin groups: B6-Min/JGMJAX, B6-Min/JGMHSD, B6-Min/DGMJAX, and B6-Min/DGMHSD. We observed significant increases in intestinal tumor multiplicity in both B6-Min groups harboring the GMHSD compared to their GMJAX counterparts, suggesting that the GM accounts for a significant portion of variability in tumor phenotype between the ApcMin sub-strains. We characterized the GMJAX and GMHSD microbial populations using 16S rRNA gene sequencing to identify potentially causative and protective bacterial taxa. Relative abundances of several taxa including Bilophila sp., Desulfovibrio sp., and Akkermansia muciniphila, were significantly elevated in GMHSD suggesting pro-tumorigenic roles, while the family Peptococcaceae was more abundant in GMJAX, indicating a potential protective role. To establish the functional output of these distinct GM profiles contributing to tumor development, we used liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to evaluate differences in the intestinal metabolome of the four experimental groups. Notably, we found that the microbiome differences due to colonization with either GMJAX or GMHSD primarily accounted for distinct metabolomic profiles, whereas host genetic differences between the sub-strains had a minimal role in shaping the metabolomes. We detected 31 putative metabolites that were significantly modulated by the GM in both the B6-Min/J and B6-Min/D sub-strains, and were therefore predictive of the relative tumor burden. Moving forward, these metabolites have implications for both biomarker discovery and potential therapeutic and preventative targets. Overall, these results provide insight regarding environmental factors influencing tumorigenesis, and further demonstrate how host-environment interactions can modulate a given disease phenotype. Citation Format: Jacob E. Moskowitz, Zhentian Lei, Susheel Busi, Marcia Hart, Craig Franklin, Lloyd Sumner, James Amos-Landgraf. Gut microbiota and metabolite-driven phenotype modulation in a mouse model of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4076.