Abstract
Simple SummaryColitis-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.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.
Highlights
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is an important public health problem [1,2]
To study the relationships associated between colon inflammation and colon carcinogenesis, we used the well-established dextran sodium sulfate (DSS)/AOM-induced colon cancer protocol to induce colon tumor formation in 8-10-week-old female BALB/c mice
No changes in mouse bodyweights were noted in the early phase of the experiment, mice in the dextran sodium sulphate/azoxymethane (DSS/AOM) group experienced gradual bodyweight declines from day 78–112, which remained stable for the duration of the experiment (Supplementary Figure S1)
Summary
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is an important public health problem [1,2]. Patients with inflammatory bowel disease are at an elevated risk for developing colon cancer [3,4,5], which is dependent on the duration, extent, and severity of inflammatory disease [6,7]. The colonic mucosa of patients suffering with active disease shows infiltration of mononuclear and polymorphonuclear leukocytes, epithelial cell erosion, crypt abscesses, and epithelial cell hyperplasia [8]. Colon carcinogenesis is a complex process that involves various interactive responses from gut mucosa, stromal cells, including immune cells and fibroblasts, and intestinal microflora, which can be further influenced by host genetic susceptibility factors and environmental elements. Immune cells in the colon have emerged as the principal effectors in the pathogenesis of IBD and colitis-associated cancer (CAC) [9,10,11]
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