Transcriptome Profiling and Metagenomic Analysis Help to Elucidate Interactions in an Inflammation-Associated Cancer Mouse Model

SIMPLE SUMMARY: Colitis-associated colorectal cancer is the third most significant condition that increases the overall risk of developing colorectal cancer. In this study, we examined normal colonic mucosa of tumor-bearing mice in the DSS/AOM mouse model by gene expression profiling and fecal samples by 16s rDNA amplicon sequencing. Gene set enrichment analysis revealed that genes associated with fatty acid metabolism, oxidative phosphorylation, and the PI3K-Akt-mTOR pathways were enriched colonic mucosa of DSS/AOM mice. Additionally, enrichment of the sphingolipid signal and lipoarabinomannan biosynthetic pathways were inferred from fecal microbial composition. Our findings provide insights into altered transcriptome and microbiome in a mouse model of colitis-induced carcinogenesis. ABSTRACT: Colitis is a risk factor for colorectal cancer (CRC) and can change the dynamics of gut microbiota, leading to dysbiosis and contributing to carcinogenesis. The functional interactions between colitis-associated CRC and microbiota remain unknown. In this study, colitis and CRC were induced in BALB/c mice by the administration of dextran sodium sulfate (DSS) and/or azoxymethane (AOM). Whole transcriptome profiling of normal colon was then performed, and gene set enrichment analysis (GSEA) revealed enriched fatty acid metabolism, oxidative phosphorylation, and PI3K-Akt-mTOR signaling in the tissues from DSS/AOM mice. Additionally, immunohistochemical staining showed increased expression levels of phosphorylated S6 ribosomal protein, a downstream target of the PI3K-Akt-mTOR pathway in the inflamed mucosa of DSS/AOM mice. Fecal microbes were characterized using 16S rDNA gene sequencing. Redundancy analysis demonstrated a significant dissimilarity between the DSS/AOM group and the others. Functional analysis inferred from microbial composition showed enrichments of the sphingolipid signal and lipoarabinomannan biosynthetic pathways. This study provides additional insights into alterations associated with DSS/AOM-induced colitis and associates PI3K-Akt-mTOR, sphingolipid-signaling and lipoarabinomannan biosynthetic pathways in mouse DSS/AOM-induced colitis.