Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development

Abstract

In recent years, the number of studies investigating the impact of the gut microbiome in colorectal cancer (CRC) has risen sharply. As a result, we now know that various microbes (and microbial communities) are found more frequently in the stool and mucosa of individuals with CRC than healthy controls, including in the primary tumors themselves, and even in distant metastases. We also know that these microbes induce tumors in various mouse models, but we know little about how they impact colon epithelial cells (CECs) directly, or about how these interactions might lead to modifications at the genetic and epigenetic levels that trigger and propagate tumor growth. Rates of CRC are increasing in younger individuals, and CRC remains the second most frequent cause of cancer-related deaths globally. Hence, a more in-depth understanding of the role that gut microbes play in CRC is needed. Here, we review recent advances in understanding the impact of gut microbes on the genome and epigenome of CECs, as it relates to CRC. Overall, numerous studies in the past few years have definitively shown that gut microbes exert distinct impacts on DNA damage, DNA methylation, chromatin structure and non-coding RNA expression in CECs. Some of the genes and pathways that are altered by gut microbes relate to CRC development, particularly those involved in cell proliferation and WNT signaling. We need to implement more standardized analysis strategies, collate data from multiple studies, and utilize CRC mouse models to better assess these effects, understand their functional relevance, and leverage this information to improve patient care.

Fig. 1

Effect of the gut microbiome on the colon epithelial cell genome and epigenome. a Enterotoxigenic Bacteroides fragilis (ETBF) and pks + Escherichia coli cause DNA damage in CECs that is mediated by B. fragilis toxin (BFT) and colibactin, respectively. Enterococcus faecalis, through impact on macrophages, induces chromosomal instability and tumor-inducing DNA mutations in cancer driver genes. b Antibiotics, germ-free mice, and specific microbes (Bifidobacterium infantis, Lactobacillus acidophilus, Klebsiella species, and ETBF) have been used to show that gut microbes induce both the hypermethylation and the hypomethylation of genes belonging to pathways that are dysregulated in colorectal cancer (CRC). c Antibiotics and germ-free mice have been used to show that gut microbes do not generally affect global chromatin structure in CECs, but do cause changes in the accessibility of transcription factor binding sites, in histone modifications, and in the location of those modified histones. These modifications often affect the promoter and enhancer regions of genes that belong to pathways that are dysregulated in CRC. d Antibiotics, germ-free mice, and specific microbes (Bacteroides acidifaciens, Lactobacillus johnsonii, and Fusobacterium nucleatum) have been used to show that gut microbes alter the expression of oncomiRNAs and anti-oncomiRNAs in CECs. They also alter the expression of long non-coding RNAs (lncRNAs) that are involved in G protein-coupled receptor (GPCR) and transforming growth factor (TGF) signaling. Abbreviations: ETS e26 transformation-specific, IRF interferon regulatory factor, miRNA microRNA, ROS reactive oxygen species, STAT signal transducer and activator of transcription