Microbial metabolites in colorectal tumorigenesis and cancer therapy

Figures & data

Table 1. SCFA-producing bacteria in human gut.

SCFAs	Bacteria	Fecal relative abundance (%)	Substrate	Bacterial genes for carbohydrate degradation
Propionate	Bacteroides fragilis	3.70556	succinate	phosphoenolpyruvate carboxykinase
	Bacteroides uniformis	7.09498	succinate	methylmalonyl-CoA decarboxylase
	Bacteroides vulgatus	9.10405	succinate	methylmalonyl-CoA decarboxylase
	Bacteroides thetaiotaomicron	2.38777	succinate	methylmalonyl-CoA decarboxylase
	Selenomonas ruminantium	0.04098	succinate	methylmalonyl-CoA decarboxylase
	Veillonella parvula	6.05763	succinate	methylmalonyl-CoA decarboxylase
	Propionibacterium freudenreichii	0.0231	succinate	succinate decarboxylase
	Propionibacterium acidipropionici	0.01208	succinate	succinate decarboxylase
	Prevotella copri	18.25712	succinate	unknown
	Alistipes putredinis	6.94845	succinate	unknown
	Dialister invisus	2.86624	succinate	methylmalonyl-CoA decarboxylase
	Dialister succinatiphilus	2.07663	succinate	methylmalonyl-CoA decarboxylase
	Phascolarctobacterium succinatutens	5.75006	succinate	methylmalonyl-CoA decarboxylase
	Blautia obeum	0.40752	succinate	propanediol dehydratase
	Bifidobacterium adolescentis DSM 20,083	0.79354	succinate	methylmalonyl-CoA decarboxylase
	Roseburia inulinivorans	0.59039	succinate	CoA-dependent propionaldehyde dehydrogenase
	Megasphaera elsdenii	0.60836	lactose	lactoyl-CoA dehydratase
	Clostridium botulinum	0.05975	lactose	lactoyl-CoA dehydratase
	Clostridium novyi	0.00719	lactose	lactoyl-CoA dehydratase
Butyrate	Faecalibacterium prausnitzi	4.06159	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Roseburia hominis	0.27651	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Roseburia intestinalis	0.6059	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Roseburia inulinivorans	0.59039	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Eubacterium hallii	0.044	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Eubacterium limosum	0.06078	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Eubacterium ramulus	0.08001	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Eubacterium ruminantium	0.11911	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Eubacterium cellulosolvens	0.065	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Eubacterium hallii	0.313	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Clostridium perfringens	5.49137	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Clostridium butyricum	7.41686	acetyl-CoA	butyrate kinase
	Anaerostipes hadrus	0.0577	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Clostridium kluyveri	0.00203	4-aminobutyrate	butyryl-CoA:4-hydroxybutyrate CoA transferase
	Anaerostipes butyraticus	0.0576	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Anaerostipes caccae	0.3643	4-aminobutyrate	butyryl-CoA:4-hydroxybutyrate CoA transferase
	Clostridium saccarobutylicum	0.08999	glutarate	butyrate kinase
	Ruminococcaceae bacterium	0.09346	glutarate	butyryl-CoA:acetate CoA-transferase
	Coprococcus catus	0.0812	acetyl-CoA	butyrate kinase
	Coprococcus comes	0.33764	acetyl-CoA	butyrate kinase
	Coprococcus eutactus	0.94995	acetyl-CoA	butyrate kinase
	Butyrivibrio crossotus	3.90884	acetyl-CoA	butyrate kinase
	Butyrivibrio fibrisolvens	0.01713	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Butyrivibrio proteoclasticus	0.01315	acetyl-CoA	butyrate kinase
	Shuttleworthia satelles	0.03472	acetyl-CoA	butyrate kinase
	Subdoligranulum variabile	0.00335	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Anaerococcus hydrogenalis	1.9246	acetyl-CoA	butyrate kinase
	Anaerococcus lactolyticus	0.0928	acetyl-CoA	butyrate kinase
	Anaerococcus prevotii	0.70814	acetyl-CoA	butyrate kinase
	Anaerotruncus colihominis	0.23757	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Megasphaera micronuciformis	0.10935	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Halanaerobium praevalens	0.00059	acetyl-CoA	butyryl-CoA:acetate CoA-transferase
	Porphyromonas asaccharolytica	0.05103	lysine	butyryl-CoA:acetoacetate CoA transferase
	Porphyromonas endodontalis	0.0106	lysine	butyryl-CoA:acetoacetate CoA transferase
	Porphyromonas gingivalis	0.0049	lysine	butyryl-CoA:acetoacetate CoA transferase
	Alkaliphilus metalliredigens	0.01554	lysine	butyryl-CoA:acetoacetate CoA transferase
	Alkaliphilus oremlandii	0.00629	lysine	butyryl-CoA:acetoacetate CoA transferase
	Fusobacterium gonidiaformans	0.09302	lysine	butyryl-CoA:acetoacetate CoA transferase
	Fusobacterium nucleatum	3.72779	lysine	butyryl-CoA:acetoacetate CoA transferase
	Carboxydibrachium pacificum	unknown	lysine	butyryl-CoA:acetoacetate CoA transferase
	Carboxydibrachium hydrogenoformans	unknown	lysine	butyryl-CoA:acetoacetate CoA transferase
Acetic acid	Bifidobacterium longum	0.3797	acetyl-CoA	acetic kinase
	Bifidobacterium animalis	0.05631	acetyl-CoA	acetic kinase
	Faecalimonas umbilicata JCM 30,896	unknown	formate	formate acetyltransferase
	Parabacteroides	5.72002	unknown	unknown
	Clostridium acetobutylicum	0.48542	acetyl-CoA	acetic kinase
	Desulfovibrio vulgaris	0.02778	unknown	unknown
	Akkermansia muciniphila	2.20562	unknown	unknown
	Bacteroides thetaiotaomicron	2.38777	acetyl-CoA	acetate kinase

Figure 1. Gut microbial metabolites in CRC development. Different metabolites are produced by microbes-mediated metabolism of various dietary components. Some microbial metabolites including SCFAs and indole derivatives are protective against colorectal tumorigenesis by regulating epigenetic modification, maintaining intestinal barrier integrity, and modulating host immunity. While other metabolites such as SBA and TMAO contribute to CRC development by activating the oncogenic WNT pathway and promoting an immunosuppressive microenvironment that favors the growth and survival of tumor cells. GPR43, G protein-coupled receptor 43; RORγt, retinoid orphan receptor γt; VEGF, vascular endothelial growth factor.

Table 2. Amino acids and lipid metabolites associated with CRC.

Type	Metabolite	Trend	Sample type	Study type	Ref
Amino acid	Lysine	up	tissue, stool	prospective	^Citation43,Citation50
	Leucine	up	tissue, stool	prospective	^Citation39
	Phenylalanine	up	tissue, stool, serum	pro/retrospective	^Citation52,Citation59
	Serine	up	tissue	retrospective	^Citation59
	Isoleucine	up	tissue, stool	prospective	^Citation39,Citation60
	Tryptophan	down	tissue	prospective	^Citation43
	Tyrosine	up	tissue, stool	prospective	^Citation50,Citation60
	glutamine	up	tissue	prospective	^Citation61
	Glutathione	up	tissue	prospective	^Citation61
	Alanine	up	tissue, stool	prospective	^Citation52,Citation60
	Taurine	up	tissue	prospective	^Citation61
	Glycine	up	stool	prospective	^Citation52
	Proline	up	stool	prospective	^Citation50
	Valine	up	stool	prospective	^Citation50
	Aspartate	up	serum	prospective	^Citation62
	Hypoxanthine	up	serum	prospective	^Citation62
	Indole-3-acetaldehyde	up	stool	prospective	^Citation52
Lipid	Sphingolipids	up	stool	prospective	^Citation63
	Lithocholic acid	up	stool, colon fluid	prospective	^Citation64
	Chenodeoxycholic acid	up	stool, colon fluid	prospective	^Citation64
	Deoxycholic acid	up	stool, colon fluid	prospective	^Citation64
	Cholic acid	up	stool	prospective	^Citation65
	Choline	up	stool	prospective	^Citation63
	Cholesterol	up	stool, serum	prospective	^Citation66,Citation67

Figure 2. Gut microbial metabolites in cancer treatment. Microbial metabolites have varied effects on cancer treatments including chemotherapy and immunotherapy. Butyrate and inosine can improve treatment efficacy against CRC by boosting the antitumor immune responses by dendritic cells and effector T cells, respectively. Meanwhile, some metabolites such as TMAO and EPS can enter the circulation and reach tumor tissues that are outside from the gut, eventually influencing treatment efficacy against these cancers. EPS, exopolysaccharides; ID2, inhibitor of DNA binding 2; IFNr, interferon production regulator.

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Data availability statement

Data is available within the article or its supplementary materials.