The roles of microbial products in the development of colorectal cancer: a review

Figures & data

Figure 1. The main mechanism of butyrate inhibiting the occurrence and development of CRC. Butyrate directly enters the cell nucleus to inhibit HDAC1, reduces SCAD level, and reduces the self-oxidation of butyrate in carcinoma cells. Butyrate accumulates in cancer cells and inhibits their proliferation. Butyrate can block the activation of HDAC3, leading to decreased phosphorylation of Akt1 and erk1/2, thereby inhibiting cell motility and ultimately CRC cell migration and invasion. Butyric acid regulates the expression of c-Myc, inhibits the transcription of miR-92a, increases the expression of PTEN, and therefore antagonizes the effect of PI3K, thereby reducing the proliferation of colon cancer cells and stimulating apoptosis. Butyrate upregulates miR-203 which directly targets HaKai, reducing its level and inhibiting cell proliferation

Figure 2. The main mechanism of BA carcinogenesis. Hydrophobic bile acids produce ROS and RNS, damage DNA and proteins, and damage BER, increasing the incidence of mutations. DCA induces PA co-localization with ERGF, promoting EGFR dimerization/multimerization and activating the MAPK cascade. activation of MAPK triggers colonic mucosal hyperproliferation, causing the development of colorectal tumors. Bile acids regulate M3R and Wnt/beta-catenin signaling and induce CSC in colonic epithelial cells, thereby inducing colon carcinogenesis

Figure 3. The main mechanism of BFT carcinogenesis. BFT up-regulates the expression level of SMOX and increases the synthesis of SMO, which promotes the conversion of spermine, which produces hydrogen peroxide causing DNA damage and apoptosis, and promotes the progression of cancer. BFT can induce cleavage of E-cadherin, trigger activation of Wnt by β-catenin nuclear localization, induce transcription and translation of c-Myc, and promote proliferation of CEC. BFT activates Stat3 to regulate Th17 cells, produce IL-17, and promote tumor development

Table 1. Factors inhibiting CRC

Origins	Products		Potential microbe	Mechanism	References
dietary fibers and starches	SCFA	Butyrate	ruminococcaceae lachnospiraceae	Function as HDAC inhibitor	20,23
				Down-regulate miR-92a expression via c-Myc	29
				Upregulates miR-203	34
		Acetate	Propionibacterium	DNA fragmentation	39,40
				Caspase-3 activation	39,40
		Propionates	Propionibacterium	Induces PRMT1 downregulation	41
BA	UDCA		Clostridium absonum, Clostridium baratii,	Decreasing the concentration of hydrophobic BA	51
				Regulate oxidative stress	52
				Up-regulates colonic MHC expression, enhancing immune surveillance	53
				Inhibits NF-κB activated	54
Unknown	Niacin		Lactobacillus acidophilus	Enhances anti-inflammatory effects by activating GPR109a	59
				Effect on CSC	63
Sulfates and other sulfur-containing compounds	H2S		Sulfate-reducing bacteria	Inhibit NF-κB signaling and increase intracellular Ca2+ concentration, leading to cell cycle arrest	101,102

CRC: colorectal cancer; SCFAs: short chain fatty acids

HDAC: histone deacetylase;

MiR-92a: microRNA-92a;

BA: bile acids

UDCA: ursodeoxycholic acid

MHC: major histocompatibility

NF-κB: NF-kappaB

GPR: G protein-coupled receptors

CSCs: cancer stem cells

H2S: Hydrogen sulfide

Table 2. Factors promoting CRC

Origins	Products	Potential microbe	Mechanism	References
BA	DCA and LCA	Clostridium, Enterococcus, Bifidobacterium, Lactobacillus	produce ROS and RNS, causing oxidative stress, and damaging DNA	69
			K-ras point mutual mutations	70
			Stimulate EGFR-MARK signaling	70
			Regulate M3R and Wnt/β-catenin signaling	78
Choline and phospholipids	TMAO	Unknown	Promotes inflammation	87
Sulfates and other sulfur-containing compounds	H2S	Sulfate-reducing bacteria	Promotes inflammation, genotoxicity, inhibits butyric acid oxidation	93–96
Bacterial toxins	B.fragilis toxin (BFT)	Enterotoxigenic bacteria fragilis (ETBF)	Induces E-cadherin lysis, resulting in loss of epithelial integrity	105
			Triggers activation of Wnt, induces c-Myc expression and promotes CEC proliferation	106
			Activates NF-κB signaling and promotes inflammation	107
			Upregulates the expression of SMOX genes, leading to DNA damage	108,109
			Activates Stat3 to regulate Th17 cells and maintain NF-κB activity	112,116
	FadA	Fusobacterium nucleatum (Fn)	Binds to CDH5, increases endothelial permeability, and allows bacteria to pass through loose junctions	117
			Binds to E-cadherin and mediates Fn adhesion and invasion of CRC cells	117
			Binding to E-cadherin inhibits its tumor suppressor activity and increases the expression of NF-κB and Wnt pathways	121
	Colibactin	E. coli and other gram-negative bacteria	Leads to double-stranded DNA breaks, chromosomal instability and cellular senescence	122,126–128
	Cytolethal distending toxin (CDT)		Causes DNA damage, leading to cell cycle arrest and cellular senescence or death	133–135

CRC: colorectal cancer

BA: bile acids

DCA: deoxycholic acid

LCA: lithocholic acid

ROS: reactive oxygen species

RNS: reactive nitrogen substances

EGFR: epidermal growth factor receptor

MAPK: mitogen activated protein kinase

TMAO: trimethylamine n-oxide

H2S: Hydrogen sulfide

BFT: fragile bacteroides toxin

ETBF: enterotoxigenic fragile bacteroides

CEC: colonic epithelial cells

SMOX: spermine oxidase

NF-κB: NF-kappaB

Fn: Fusobacterium nucleatum

CDT: cytolethal distending toxin