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Integrated metabolome and transcriptome analyses provide novel insight into colon cancer modulation by the gut microbiota

ABSTRACT: Colon cancer onset and progression is strongly associated with the presence, absence, or relative abundances of certain microbial taxa in the gastrointestinal tract. However, specific mechanisms affecting disease susceptibility related to complex commensal bacterial mixtures are poorly understood. We used a multi-omics approach to determine how differences in the complex gut microbiome (GM) influence the metabolome and host transcriptome and ultimately affect susceptibility to adenoma development. Fecal samples collected from a preclinical rat model of colon cancer harboring distinct complex GMs were analyzed using ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS). We collected samples prior to observable disease onset and identified putative metabolite profiles that predicted future disease severity, independent of GM status. Transcriptome analyses performed after disease onset from normal epithelium and tumor tissues between the high and low tumor GMs suggests that the GM is also correlated with altered host gene expression. Integrated pathway (IP) analyses of the metabolome and transcriptome based on putatively identified metabolic features indicate that bile acid biosynthesis was enriched in rats with high tumors (GM:F344) along with increased fatty acid metabolism and mucin biosynthesis. These data emphasize the utility of using untargeted metabolomics to reveal signatures of susceptibility and resistance and integrated analysis reveals common pathways that are likely to be universal targets for intervention.

ORGANISM(S): Rat Rattus Norvegicus

TISSUE(S): Feces

DISEASE(S): Cancer

SUBMITTER: Susheel Bhanu Busi

PROVIDER: ST001075 | MetabolomicsWorkbench | Wed Oct 10 00:00:00 BST 2018

REPOSITORIES: MetabolomicsWorkbench

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Project description:Background: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors which have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. Results: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression Quantitative Trait Loci (eQTLs) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTLs are detected for several genes associated with tumor susceptibility, including Interleukin 18, Granzyme E, Sprouty homolog 2, and MAP kinase kinase 4. Conclusions: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, MAP kinase signaling, and cancer susceptibility. A backcross was generated using male Mus spretus and female FVB/N mice; female F1 hybrids were mated with male FVB/N mice. Backcross mice (8-12 weeks old) received a single dose of DMBA (25 µg per mouse in 200 µl acetone). Starting one week after the initiation tumors were promoted with TPA (200 µl of 10-4 M solution in acetone) twice weekly for 20 weeks. Initiation and promotion were performed on doral back skin. DNA from 62 Carcinomas and matched untreated tails (used for normal DNA comparison) was obtained from tissue that was snap frozen when animals were sacrificed.

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Integrated metabolome and transcriptome analyses provide novel insight into colon cancer modulation by the gut microbiota

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