Microbiota impact on the epigenetic regulation of colorectal cancer

Abstract

Mechanisms of colorectal cancer (CRC) development can be generally divided into three categories: genetic, epigenetic, and aberrant immunologic signaling pathways, all of which may be triggered by an imbalanced intestinal microbiota. Aberrant gut microbial composition, termed 'dysbiosis', has been reported in inflammatory bowel disease patients who are at increased risk for CRC development. Recent studies indicate that it is feasible to rescue experimental models of colonic cancer by oral treatment with genetically engineered beneficial bacteria and/or their immune-regulating gene products. Here, we review the mechanisms of epigenetic modulation implicated in the development and progression of CRC, which may be the result of dysbiosis, and therefore may be amenable to therapeutic intervention.

Keywords: colorectal cancer; commensal bacteria; epigenetic regulation; inflammatory bowel disease; microbiota.

Figure 1. Mechanisms for maintaining basal immune activation and tolerance

A. Commensal bacteria help to preserve a healthy gut environment. Abundant beneficial microbes exist at the mucosal layer where epithelial cells can be stimulated by bacterial antigens such as surface layer proteins and metabolic products. The release of signaling molecules or the presentation of antigens by dendritic cells is able to induce the activation of T and B lymphocytes, meanwhile recruiting more dendritic cells and macrophages. B. Bacterial fermentation products such as SFCAs inhibit the NF-κB signaling pathway and decrease HDAC activity to regulate homeostasis. HATs, acting as transcription co-activators, can open chromosome structure by adding acetyl residues to histones, while HDACs do the opposite. Inhibition of HDACs may lead to accessible chromatin. The transcription of cell cycle arrest and apoptosis-related genes can result in suppression of tumor development. Inhibition of the NF-κB signaling pathway prevents its contribution to pathogenic inflammation as well. SlpA, Surface Layer Protein A; SFCA, Short Fatty Chain Acid; HAT, Histone Acetyltransferase; HDAC, Histone Deacetylase

Figure 1. Mechanisms for maintaining basal immune activation and tolerance

A. Commensal bacteria help to preserve a healthy gut environment. Abundant beneficial microbes exist at the mucosal layer where epithelial cells can be stimulated by bacterial antigens such as surface layer proteins and metabolic products. The release of signaling molecules or the presentation of antigens by dendritic cells is able to induce the activation of T and B lymphocytes, meanwhile recruiting more dendritic cells and macrophages. B. Bacterial fermentation products such as SFCAs inhibit the NF-κB signaling pathway and decrease HDAC activity to regulate homeostasis. HATs, acting as transcription co-activators, can open chromosome structure by adding acetyl residues to histones, while HDACs do the opposite. Inhibition of HDACs may lead to accessible chromatin. The transcription of cell cycle arrest and apoptosis-related genes can result in suppression of tumor development. Inhibition of the NF-κB signaling pathway prevents its contribution to pathogenic inflammation as well. SlpA, Surface Layer Protein A; SFCA, Short Fatty Chain Acid; HAT, Histone Acetyltransferase; HDAC, Histone Deacetylase

Figure 2. Interactions between the gut microbiota and the immune system maintain healthy homeostasis

Either alteration of the gut microbiota composition or overactivation of the immune system may disrupt the balance, and therefore, induce inflammation and even IBD or CRC. IBD, Inflammatory Bowel Disease; UC, Ulcerative Colitis; CRC, Colorectal Cancer

Figure 3. Genetic and epigenetic mechanisms of CRC pathogenesis

Mutation of genes (e.g., APC) involved in the Wnt signaling pathway plays a dominant role in CRC pathogenesis. Genes that are related to cell cycle progression, DNA repair, and cytokine signaling have also been shown to be crucial for CRC pathogenesis. DNA hypermethylation of tumor suppressor gene promoter regions has been intensively studied to demonstrate its pivotal role in gene silencing. Histone modification includes histone methylation and deacetylation, both of which have been shown to be associated with DNA methylation.

Figure 4. Cascade of molecular reactions initiated by LTA-deficient L. acidophilus

Either component proteins or metabolic products from LTA-deficient L. acidophilus are potential antigens that can be recognized by dendritic cells. Presentation of antigen to recipient CD4⁺ T cells induced the genesis of a population of Tregs that could further differentiate into Th17 or Th1 cells, depending on the microenvironment. Meanwhile, several signaling pathways were triggered in dendritic cells by the recognition of antigens. The MAPK-Erk1/2 pathway was shown to be crucial for the expression of the anti-inflammatory cytokine IL-10, and tumor suppressors, such as RUNX3 and TIMP3, were also upregulated by the treatment of LTA-deficient L. acidophilus both in vitro and in vivo. RNAP II, RNA Polymerase II; TIC, Transcription Initiation Complex.