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Table 1 Overview of microbiome and specific microbe associations with colorectal cancera

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

Microbiome or single microbes CRC associations CRC animal models CRC pathways Effects on the genome or epigenome
Microbiome composition Results are variable but several groups of microbes are found more frequently in CRC patients than normal controls: microbes associated with periodontal disease [6], human oral microbes (Fn, Pm, Ps, and Gm) [7,8,9], Klebsiella, Enterococcus, Escherichia/Shigella, Streptococcus, and Peptostreptococcus [4]. Several species are found with increasing frequency as tumor stage progresses from healthy tissue to advanced adenoma (Bd and Bm) or from advanced adenoma to carcinoma (Bo and Bv) [5] In an AOM mouse model of CRC, inoculation of mice with human gut microbial communities produces variable amounts of tumor formation associated with microbiome composition [23], and perhaps with donor CRC status [24] Inoculation of mice with human gut microbial communities leads to increased expression of proinflammatory cytokines, increased expression of genes involved in proliferation, apoptosis, stemness, invasiveness and metastasis, and/or increased Th1 and Th17 cell populations [24] Use of antibiotics and GF mice has previously suggested a role for gut microbe-induced methylation changes in specific genes and expression changes in miRNAs [131,132,133,134,135]
Microbiome organization In humans, invasive polymicrobial bacterial biofilms are present more frequently on right-sided tumors than on left-sided tumors [3, 7] Not yet identified The presence of invasive polymicrobial bacterial biofilms in humans is associated with decreased E-cadherin protein detection, increased IL-6 protein expression, increased STAT3 activation, and increased cell proliferation in CECs [3] Not yet identified
ETBF ETBF is found more frequently in individuals with CRC than in healthy controls [11,12,13] In an Apcmin/+ mouse model of CRC, ETBF inoculation results in an IL-17-dependent increase in tumorigenesis in the distal colon [27] Inoculation of mice with ETBF leads to a proinflammatory immune environment characterized by STAT3 activation, IL-17-dependent NF-κB activation, increased WNT/β-catenin signaling, E-cadherin cleavage, and increased CEC proliferation [29,30,31, 33] In Apcmin/+ mice, ETBF induces enrichment of EZH2 and DNMT1 at promoter CpG islands of specific genes in inflamed distal CECs [122]. BFT induces CEC DNA damage, possibly through the induction of spermine oxidase with generation of ROS [136]
pks + Escherichia coli pks + E. coli are found more frequently in individuals with CRC than in healthy controls [14, 15], more frequently in tumors than in normal flanking tissue [14], and more frequently in late-stage tumors than in early-stage tumors [14] In conventional and GF Il10−/−/AOM mouse models of CRC, pks + E. coli induce tumor formation [25, 26] Not yet identified pks + E. coli genotoxin colibactin crosslinks DNA, leading to dsDNA breaks and CIN [55, 56, 137]
Fusobacterium nucleatum When compared to normal colon tissue, fusobacteria are found more frequently in adenoma samples [7, 17], colon tumor samples with high-grade dysplasia [20], carcinoma samples [16, 18], and even distant CRC metastases [19]. Fn was identified as the dominant species in many of these studies, although the impact of the four subspecies of Fn is uncertain In a conventional Apcmin/+ mouse model of CRC, Fn increases tumor formation, whereas in a GF Il10−/− mouse model of CRC or a T-bet−/−/Rag2−/−mouse model of CRC, Fn has no effect on tumor formation [16] Inoculation of mice with Fn leads to increased β-catenin signaling in CECs, increased cell proliferation, myeloid cell accumulation, and the induction of proinflammatory cytokines [32] See text and Table 2
Streptococcus gallolyticus Sg bacteremia is strongly associated with colon tumor presence. Sg is found more frequently in tumors than in surrounding normal tissue [21, 22] In a mouse xenograft model of CRC, Sg promotes tumor growth. In an AOM mouse model of CRC, Sg promotes tumor development [28] Inoculation of mice with Sg leads to increased β-catenin nuclear localization, and to increased expression of c-Myc and cyclin D1 proteins [28] Not yet identified
Enterococcus faecalis Not yet identified In an Il10−/−mouse model, colonization with superoxide-producing Ef leads to cancer formation [138] Ef activates WNT/β-catenin signaling and transcription factors associated with CRC stem cells through a bystander effect [139] See text and Table 2
  1. aThis table provides a summary of the associations between various microbes or microbial communities and colorectal cancer (CRC). Epidemiologic data, in vivo animal experiments, and key pathways associated with CRC are presented. Also, specific genome or epigenome effects that do not fall within the scope of the articles reviewed (studies examining direct effects of gut microbes on CECs, 2015–present) are highlighted. Abbreviations: AOM azoxymethane, Bd Bacteroides dorei, Bf Bacteroides fragilis, BFT Bacteroides fragilis toxin, Bm Bosea massiliensis, Bo Bacteroides ovatus, Bv Bacteroides vulgatus, CEC colon epithelial cell, CIN chromosomal instability, DNMT1 DNA methyltransferase 1, dsDNA double-stranded DNA, Ef Enterococcus faecalis, ETBF enterotoxigenic Bacteroides fragilis, EZH2 Enhancer of Zeste protein-2, Fn Fusobacterium nucleatum, Gm Gemella morbillorum, Pm Parvimonas micra, Ps Peptostreptococcus stomatis, ROS reactive oxygen species, Sg Streptococcus gallolyticus, STAT3 signal transducer and activator of transcription 3