Table 2.

Cytotoxic/genotoxic mechanisms of endogenous molecules and compounds generated by intestinal bacteria that could be involved in CRC. Direct mechanisms refer to those that promote genotoxic and/or cytotoxic action directly. Indirect mechanisms are those that cause damage at different levels, from which a cytotoxic and/or genotoxic action is derived.

Main Mechanism		Molecules/Compounds Involved	Microbial Group	Experimental Approach Used for Study	Mode of Action	Ref.
Direct mechanisms	Genotoxins	Typhoid toxin	Salmonella enterica serovar Typhi	In vitro and animal models	DNAse activity; induction of symptoms characteristic of typhoid fever	[64]
		Cytolethal distending toxin	Proteobacteria	Cell lines and primary cell and mouse models of chronic infections	DNase activity; Proinflamation and carcinogenic potential	[65,66,67]
		Colibactin	Escherichia coli group B	Eukaryotic cells	DNA double-strand breaks	[68]
				Epidemiological and animal model	DNA double-strand breaks in vitro and in vivo; enhanced tumour growth by senescence	[69,70]
	Alteration of host cellular cycle	Cytotoxin-associated gene A Vacuolating cytotoxin A	Helicobacter pylori	Molecular, experimental and epidemiological	DNA damage; Increases IL-8; produces reactive oxygen species (ROS) and nitric oxide; increases concentrations of cyclo-oxygenase 2; decreases apoptosis; and increases cell proliferation	[66,71]
		Enterotoxin	Bacteroides fragilis	In vitro and epidemiological	DNA damage; high levels of ROS; Diarrheal disease, associated with colorectal cancer	[62,72]
		Adhesin A	Fusobacterium nucleatum	In vitro and epidemiological	Activation of β catenin pathway	[66,73]
		ExoS exotoxin	Pseudomonas aeruginosa	In vitro, experimental and epidemiological	Activation of pathways with final mechanism leading to DNA damage; unknown mechanisms in cancer generation	[62,66]
		Cysteine protease-like	Shigella flexneri	In vitro and epidemiological	Potassium outflow conducting to ROS production; induce degradation of p53; DNA damage; dysentery	[62,66]
		Avirulence protein A	Salmonella enterica	In vitro and mouse model of inflammation-associated cancer	Target β-catenin pathway; colonic tumorigenesis and tumour progression	[66]
		Cytotoxic necrotising factor	Escherichia coli	In vitro and animal models	Activates Rho GTPase; modifies cytoskeleton; triggers G1-S transition; downregulate mismatch repair genes; the role of CNF in infections in not clear	[71,74]
		Cycle-inhibiting factor		In vitro	Inhibition of mitosis	[75]
		Secondary bile acids	Anaerobic bacteria with 7-α dehydroxylation activity of primary bile acids	In vitro colon cells and animal models	Changes in physicochemical membrane properties; Apoptosis and genomic damage by ROS; Deoxycholic acid is carcinogenic at high doses and long-term treatment in animal models	[76]
Indirect mechanisms	Oxidative stress	Reactive oxygen species	Peptostreptococcus anaerobius	In vivo, in vitro and epidemiological	Increase of human colon tumour tissues and adenomas; these bacteria increase colon dysplasia in a mouse model of CRC by induction of ROS levels, which promotes cholesterol synthesis and cell proliferation.	[77]
			Enterococcus faecalis	In vitro and in vivo models, epidemiological	Induction of ROS, activation of macrophages; promotion of tumorigenesis	[66,78]
			Faecal matrix	In vitro	Unknown reducing agent	[79]
	Formation of H2S	H2S	Sulfate-reducing bacteria	Epidemiological and in vitro models	Promotes instability or cumulative mutations in a predisposed genetic background	[80]
	Inflammation	Wall-extracted antigen	Streptococcus bovis	Epidemiological and molecular	Activation of cyclo-oxygenase 2, interleukin 8 production, and cell proliferation	[71]
	Disabling cellular DNA repair process	Listeriolysin O	Listeria monocytogenes	In vitro and epidemiological	Pore formation in intestinal host cells; Prevention of recruitment of repair complex to DNA breaks; listeriosis	[66]
		Secreted effector protein EspF	Escherichia coli	In vitro	Down-regulation DNA mismatch repair	[66]
	Protein metabolism	Phenol/indol/p-cresol/	Intestinal bacteria	Colonic cells	Increased anion superoxide production and genotoxic effects	[81,82]
		Fecapentanes	Bacteroides sp.	In vitro; In vivo	Cytotoxic and mutagenic effects via ROS production; Controversial in vivo effect	[63,83]
		Ammonium	Intestinal bacteria	In vitro	Antiproliferative effect without decrease of cell viability	[84]