Microbiome and colorectal carcinogenesis: Linked mechanisms and racial differences

Table 1 Gut and gastric microbiota associated with cancer development

Gut bacteria	Bacterial machinery	Hallmarks of cancer including enabling characteristics affected	Outcome	Methods	Ref.
Fusobacterium nucleatum	FadA	Tumor-promoting inflammation	Expression of NF-κB and pro-inflammatory cytokines IL-6, 8, and 18	HCT116 cells (expressing E-cadherin)	[56,57]
	Unknown	Tumor-promoting inflammation	Infiltration of specific myeloid cell subsets and an NF-κB proinflammatory signature (shared with human CRC tissue with a high Fusobacterium abundance)	Apc(Min/+) mice fed F. nucleatum	[39]
	Unknown	Tumor-promoting inflammation	TNF-α and IL-10 abundance	Rectal biopsies of adenoma cases compared to controls	[59]
	Unknown	Tumor-promoting inflammation	Cytokine production, which is mediated by the p38 MAPK signaling but independent of TLRs, NOD-1, NOD-2 and NF-ĸB signaling	HEK293T cells, (which lack endogenous TLRs)	[58]
	Fap2	Avoiding immune destruction	Fap2 interacted with TIGIT, leading to the inhibition of NK cell cytotoxicity	Various BW cells	[31]
	Unknown	Avoiding immune destruction	MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity	Colorectal carcinoma tissues (stages I-IV) from Japanese patients	[66]
	Generation of formyl-methionyl-leucyl-phenylalanine and SCFAs from dietary amino acids	Deregulating cellular energetics	Chemoattract myeloid cells	ApcMin/+ mouse model of intestinal tumorigenesis	[39]
	Adhesin FadA	Sustaining proliferative signaling	FadA binds to E-cadherin and activates β-catenin signaling	HCT116 cells (expressing E-cadherin)	[56]
	Unknown	Genome instability and mutations	CpG island methylating phenotype (CIMP), microsatellite instability (MSI), and MLH1 hypermethylation	Colorectal carcinoma tissue	[82]
Streptococcus galloyticus (S. bovis)	Unknown	Tumor-promoting inflammation	Increase in the production of IL-8 in the colonic mucosa. Study suggests that bacteria act as a promoter of early preneoplastic lesions in the colon of rats	Male rats pre-treated with the carcinogen azoxymethane (AOM)	[64]
	Unknown	Tumor-promoting inflammation	Induce mRNA expression of proinflammatory cytokines, IL-1	Colorectal mucosa and tumors of CRC patients with and without a history of S. gallolyticus bacteremia in the last 2 years	[87]
	Wall extracted antigens (WEA) and whole bacteria	Sustaining proliferative signaling	MAPKs activation which up-regulate the expression of COX-2	Human colonic epithelial Caco-2-cells	[36]
	Unknown	Inducing angiogenesis	Induce mRNA expression of angiogenic chemokine, IL-8	Feces and colorectal tissue of CRC patients with and without a history of S. gallolyticus bacteremia in the last 2 years	[87]
	WEA and whole bacteria	Inducing angiogenesis	Over-expression of COX-2	Human colonic epithelial Caco-2-cells	[36]
	Unknown	Resisting cell death	mRNA expression of proinflammatory cytokines, IL-1 and COX-2, as well as angiogenic chemokine, IL-8	Feces and colorectal tissue of CRC patients with and without a history of S. gallolyticus bacteremia in the last 2 years	[87]
	Unknown	Resisting cell death	Higher IL-8 mRNA and NF-κB mRNA in tumorous than non-tumorous tissue sections of adenoma and carcinoma.	Serum and tissue of CRC, CRA and healthy volunteers	[88]
	WEA and whole bacteria	Resisting cell death	Over-expression of COX-2	Human colonic epithelial Caco-2-cells	[36]
Enterotoxigenic Bacteroides fragilis	B. fragilis toxin (BFT)	Tumor-promoting inflammation	Activation of STAT3 initiates a Th17 mucosal immune response	ApcMin/+ mouse model of intestinal tumorigenesis	[53]
	BFT	Sustaining proliferative signaling	E-cadherin cleavage then β-catenin nuclear signaling is expressed and induces c-Myc translation	HT29/C1 cells	[94]
	BFT	Sustaining proliferative signaling	Induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation	Specific pathogen-free (SPF) C57BL/6J or germfree mice	[74]
	BFT	Genome instability and mutations	NF-κB and mitogen-activated protein kinases (MAPKs)	HT29/C1 cells	[94]
	BFT	Genome instability and mutations	SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage	HT29/c1 and T84 colonic epithelial cells	[98]
E. coli	Cyclo-modulins (CM)	Sustaining proliferative signaling	Increases in proliferating cell nuclear antigen (PCNA) mRNA levels	CEACAM-expressing mice	[80]
	Colibactin-producing (pks+)	Sustaining proliferative signaling	Accumulation of SUMO-conjugated p53 and production of hepatocyte growth factor (HGF) by targeting targets SENP1 (senescence-associated secretory phenotype)	AOM/IL-10-/- (azoxymethane/interleukin) mouse model	[81]
	CM	Genome instability and mutations	genotoxin-encoding genes in mucosa	Analysis of mucosa of patients with CRC	[79]
Enterococcus fecaelis	Unknown	Genome instability and mutations	Macrophage COX-2 is induced by superoxide and propagate genomic instability	Hybrid hamster cells [A(L)N] containing human chromosome 11 and a dual-chamber tissue culture model	[100]
	Enterococcus faecalis-infected macro-phages, or purified trans-4-hydroxy-2-nonenal (4-HNE)-an endogenous mutagen and spindle poison produced by macrophages	Genome instability and mutations	Double-stranded DNA breaks, tetraploidy and chromosomal instability (CIN)	Primary murine colon epithelial cells growth as allografts in immunodeficient mice	[99]
	Unknown	Genome instability and mutations	Epithelial cell DNA damage through the production of extracellular O2-	HT-29 intestinal epithelial cells and a rat intestinal colonization model	[12]
H. pylori	cagA	Tumor-promoting inflammation	Upregulation of COX-2 and prostaglandin E2	Analysis of serum IgG antibodies against H. pylori (ELISA) and cagA protein (Western blot assay) in patients with colon cancer	[62]

COX-2: Cyclooxygenase-2; H. pylori: Helicobacter pylori; CIN: Chromosomal instability; CRC: Colorectal cancer; HGF: Hepatocyte growth factor; BFT: Bacteroides fragilis toxin; CM: Cyclo-modulins; SATA3: Signal transducer and activator of transcription 3; MSI: Microsatellite instability; PCNA: Proliferating cell nuclear antigen; TLRs: Toll-like receptors; cagA: Cytotoxin-associated gene; S. gallolyticus: Streptococcus gallolyticus; S. bovis: Streptococcus bovis.