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Table 2 Summary of recent papers (2015–present) addressing the impact of gut microbes on the colon epithelial cell genome or epigenome

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

Key findings Bacteria studied Model system Relevant CRC genes or pathways identified Technique used to examine genome or epigenome
DNA damage
 Colibactin-induced intrastrand DNA crosslinking upon exposure to cells [57] pks + E. coli HeLa cells None highlighted Cross-linking assay in cells, acellular DNA-cross-linking assay
pks + E. coli worked synergistically with ETBF to cause increased DNA damage and increased tumor formation in a mouse model of CRC [59] pks + E. coli and ETBF Mice None highlighted Immunohistochemistry
 When inoculated with ETBF, Apcmin/+/Msh2−/− mice produced more tumors than Apcmin/+ mice. The increase in tumor burden was not seen in the absence of ETBF inoculation, suggesting that MMR proteins are important in preventing tumorigenesis after ETBF infection [61] ETBF Mice None highlighted Transgenic mouse model
 CECs exposed to macrophages that were previously exposed to E. faecalis showed an increased rate of mutagenesis and an increased rate of aneuploidy and chromosomal translocation, indicative of CIN [63] E. faecalis Young adult mouse colonic (YAMC) ECs Several cancer driver genes, including Arid1b, Cdkn2a, Daxx, Gata3, Map3k1, Notch1, Pten, Smad2 and others Mutant fraction assay, FACS
 In a porcine model, in which premature infant pigs were given antibiotics immediately after birth, 80 DMRs were identified and were associated with genes involved in phagocytosis, the innate immune response, and other pathways [73] Antibiotic-treated porcine gut microbiome Premature infant pigs Pathways related to innate immune response and phagocytosis RRBS, BSP
 Treatment of human intestinal ECs with Lactobacillus acidophilus, Bifidobacterium infantis, and Klebsiella species resulted in methylation changes in several hundred genes of interest [74] L. acidophilus, B. infantis and Klebsiella species Human intestinal EC lines (H4 and NCM460) Pathways related to nucleotide binding (immature ECs) and chromatin organization (mature ECs) Infinium Human Methylation 450 BeadChip
 Fecal microbial transplant to reintroduce microbes into GF mice resulted in increased gene methylation [75] Murine gut microbiome Mice None highlighted Bisulfite pyrosequencing
 The gene methylation status of GF mice differed from that of conventional mice. The number of genes with changes in both gene expression and methylation status increased as mice aged [76] Murine gut microbiome Mice Pathways related to cellular proliferation or regeneration (Pik3cd, Rb1, Grb10, Plagl1, Nfix, Tab3) and immune response (Atp7a, Atf4, Bcl3) RRBS
 ETBF-induced tumors contained more hypermethylated DMRs and fewer hypomethylated DMRs than spontaneous tumors [61] ETBF Mice Hoxa5, Polg, Runx1, Runx3, CD37, Stx11, Tceb2, Lgr6, Cdx1, and Fut4 genes MBD-seq, pyrosequencing, qMSP
Chromatin structure
 Investigators found no differential DNase hypersensitivity sites in the jejunum of GF mice. They did, however, find changes in the histone marks H3K4me1 and H3K27ac, which are generally enriched at poised or active enhancers, respectively [87] Murine gut microbiome Mice Transcription factors belonging to the IRF family, STAT family, and ETS family DNase-seq, ChIP-seq
 Several hundred promoters and enhancers lost rhythmicity after antibiotic treatment, and a near equal number gained de novo rhythmic behavior [92] Antibiotic-treated murine gut microbiome Mice None highlighted ChIP-seq
 Bacterial presence resulted in numerous changes in histone acetylation and methylation in the proximal colon tissue of GF mice. SCFAs produced by gut microbes might have mediated this effect [93] Murine gut microbiome Mice None highlighted Electrospray ionization tandem mass spectrometry
 The location of H3K4 methylation marks was modified when gut microbes colonized GF mice [94] Murine gut microbiome Mice Genes involved in maintaining the innate mucosal barrier, ROS generation, ephrin signaling, and others ChIP-seq
 In mice treated with antibiotics for 3 days, H3K18 crotonylation in the colon was decreased. This was associated with a concomitant decrease in HDAC2 protein expression, which was mediated by the SCFAs butyrate and crotonate. These SCFAs promote H3K18 crotonylation by inhibiting HDACs [96] Antibiotic-treated murine gut microbiome Mice, mouse small intestinal enteroids, human CRC cell lines (HCT116) Pathways related to endometrial cancer, prostate cancer, pancreatic cancer, CRC, TGF-β signaling and stem cell pluripotency ChIP-seq
Non-coding RNAs
 Using GF mice, the presence of gut microbes was associated with decreased production of miRNAs, which were shown to be produced by intestinal ECs, goblet cells and Paneth cells [107] Murine gut microbiome Mice None highlighted NanoString nCounter
 Absence (GF mice) of the gut microbiota resulted in lower levels of expression of the miRNAs let-7b, miR-141, and miR-200a. Depletion (antibiotic-treated rats) of gut microbiota resulted in lower levels of miRNAs let-7b, miR-141, miR-200a, and miR-1224 after 6 weeks of treatment [108] Murine gut microbiome, antibiotic-treated murine gut microbiome Mice, rats let-7b, miR-141, miR-200a, and miR-1224 qRT-PCR
miR-21-5p was expressed at higher levels in the small and large intestine of conventional mice than in GF mice. Exposing HT-29 and SW480 cells (two CRC cell lines) to Bacteroides acidifaciens type A43 and Lactobacillus johnsonii 129 resulted in an upregulation of miR-21-5p [112] Murine gut microbiome, B. acidifaciens type A43 and L. johnsonii 129 Mice, human CRC cell lines (HT-29, SW480) miR-21-5p Microarray
 19 miRNAs were differentially expressed in IESCs of GF mice when compared to conventionalized mice. miR-375-3p was downregulated in conventionalized mice [115] Murine gut microbiome Mice, mouse small intestinal enteroids miR-375-3p RNA-seq
 Several miRNAs were downregulated in Fusobacterium nucleatum-rich tumor samples from patients with recurrent CRC. A CRC xenograft model was used to show that F. nucleatum causes resistance to oxaliplatin and 5-FU via downregulation of miR-4802 and miR-18a* [117] F. nucleatum Mice, CRC cell lines (HCT116 and HT29) miR-4802 (newly associated with CRC) and miR-18a* (belongs to the miR-17-92 cluster) RNA-seq
 lncRNAs in the mouse duodenum, jejunum, ileum, and colon were altered in GF mice when compared to conventional mice [118] Murine gut microbiome Mice Pathways related to GPCR signaling and TGF signaling RNA-seq
 When GF mice were reconstituted with normal mouse microbiota or with E. coli alone, fairly distinct changes in lncRNA signatures occurred, with only 8% of the differentially expressed lncRNAs overlapping [119] Murine gut microbiome, E. coli Mice None highlighted Affymetrix mouse exon microarray
  1. Abbreviations: BSP bisulfite sequencing PCR, CEC colon epithelial cell, ChIP chromatin immunoprecipitation, CIN chromosomal instability, DMR differentially methylated region, ETBF enterotoxigenic Bacteroides fragilis, EC epithelial cell, ETS e26 transformation specific, GF germ-free, FACS fluorescence-activated cell sorting, GPCR G-protein-coupled receptor, HDAC histone deacetylase, IESC intestinal epithelial stem cell, IRF interferon regulatory factor, lncRNA long non-coding RNA, MBD methyl CpG binding domain, miRNA microRNA, MMR mismatch repair, qMSP quantitative methylation-specific PCR, ROS reactive oxygen species, RRBS reduced representation bisulfite sequencing, SCFA short chain fatty acid, STAT signal transducer and activator of transcription, YAMC young adult mouse colonic