Role of the Gut Microbiota and Its Metabolites in Tumorigenesis or Development of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the most common cancer of the digestive system with high mortality and morbidity rates. Gut microbiota is found in the intestines, especially the colorectum, and has structured crosstalk interactions with the host that affect several physiological processes. The gut microbiota include CRC-promoting bacterial species, such as Fusobacterium nucleatum, Escherichia coli, and Bacteroides fragilis, and CRC-protecting bacterial species, such as Clostridium butyricum, Streptococcus thermophilus, and Lacticaseibacillus paracasei, which along with other microorganisms, such as viruses and fungi, play critical roles in the development of CRC. Different bacterial features are identified in patients with early-onset CRC, combined with different patterns between fecal and intratumoral microbiota. The gut microbiota may be beneficial in the diagnosis and treatment of CRC; some bacteria may serve as biomarkers while others as regulators of chemotherapy and immunotherapy. Furthermore, metabolites produced by the gut microbiota play essential roles in the crosstalk with CRC cells. Harmful metabolites include some primary bile acids and short-chain fatty acids, whereas others, including ursodeoxycholic acid and butyrate, are beneficial and impede tumor development and progression. This review focuses on the gut microbiota and its metabolites, and their potential roles in the development, diagnosis, and treatment of CRC.

Keywords: colorectal cancer; gut microbiota; intratumoral microbiota; metabolite; probiotic bacteria; tumorigenesis.

Figure 1

The role of the gut microbiota in CRC progression through immune, inflammatory, and metabolic reactions. Several bacterial species in the gut could induce the host to produce chemokines including chemokine (C‐C motif) ligand 5 (CCL5), chemokine (C‐X‐C motif) ligands 9 (CXCL9), and CXCL17. Tumor cells accumulate T cells that promote inflammation and leads to progression of CRC. Microbial antigens produced by the gut microbiota could activate signaling through various receptors including nucleotide‐binding oligomerization‐like receptor (NLR), retinoic acid‐inducible gene I‐like receptor (RLR), toll‐like receptor (TLR), and absent in melanoma 2‐like receptor (AIMR), that stimulate the immune response.

Figure 2

Promoting effects of gut microbiota metabolites on CRC. Metabolites including several bile acids (e.g., DCA and LCA), and trimethylamine n‐oxide (TMAO) promote CRC development by increasing cancer cell proliferation, increasing DNA damage, enhancing tumor invasion and metastasis, reducing cell–cell adhesion, and promoting genomic instability.

Figure 3

Protective roles of gut microbiota metabolites against CRC. Metabolites including bile acids such as ursodeoxycholic acid (UDCA), SCFAs such as butyrate, and amino acids play a protective role by assembling the tight junction, inhibiting inflammation, promoting cancer cell apoptosis, and protecting colon epithelial barriers, to inhibit growth of CRC.

Figure 4

The role of gut microbiota in CRC diagnosis and treatment. Detection of fecal bacteria including F. nucleatum, serum antibodies against F. nucleatum and gut microbiota metabolites including BAs and SCFAs could play roles in CRC screening. Fecal bacteria including two species of Bacteroides, Lachnospiraceae, Clostridiales, and Clostridium could be used to detect adenomas. F. nucleatum can be used in prognostic predictions for CRC patients. Treatment methods including chemotherapy, immunotherapy, and radiotherapy could disturb microbial community, while the composition of the gut microbiota could, in turn, affect the treatments. Methods including supplementation with probiotics, prebiotics and their metabolites, and fecal microbiota transplantation (FMT) could modify gut microbiota composition in order to treat CRC.