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 |