Influence of the microbiota on epigenetics in colorectal cancer

Abstract

Colorectal cancer is one of the most common malignancies and is the second leading cause of cancer death worldwide. Generally, there are three categories of colorectal cancer development mechanism-genetic, epigenetic and aberrant immunological signaling pathways-all of which may be initiated by an imbalanced gut microbiota. Epigenetic modifications enable host cells to change gene expression without modifying the gene sequence. The microbiota can interact with the host genome dynamically through the interface presented by epigenetic modifications. In particular, bacterially derived short-chain fatty acids have been identified as one clear link in the interaction of the microbiota with host epigenetic pathways. This review discusses recent findings relating to the cross talk between the microbiota and epigenetic modifications in colorectal cancer.

Keywords: colorectal cancer; epigenetics; gut microbiota; short-chain fatty acids.

Figure 1.

The gut microbiota influences epigenetic modifications in colorectal carcinogenesis. Commensal bacteria, such as Clostridia, can induce colonic pTregs via their fermentation product, butyrate, an HDAC inhibitor, which enhances histone H3 acetylation in the promoter and CNS1 of the Foxp3 locus. Meanwhile, acetate and propionate promote the accumulation of colonic Treg cells by activating GPR43. Both induce colonic Foxp3⁺CD4⁺Treg cells, which have a key role in limiting inflammatory responses during carcinogenesis. Butyrate increases histone methylation in the promoter of NF-κB1, thus downregulates expression of NF-κB1. SCFAs induce the epithelial anti-inflammatory IL-10 receptor alpha subunit (IL-10RA) mRNA and antimicrobial peptides (AMPs) via their HDAC inhibitor functions. Thus, together with reduced NF-κB1, SCFAs inhibit colonic inflammation through epigenetic modification. In colon cancer cells, miRNAs alter the abundance of bacteria, such as F. nucleatum and E. coli. In contrast, bacteria (e.g. L. mesenteroides) can also influence the expression levels of miRNAs in colon cancer cells. In addition, commensal bacteria can influence gene expression by increasing DNA methylation at multiple CpG sites in colorectal cancer cells.