The role of microbiota in the development of colorectal cancer

Abstract

Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation.

Keywords: carcinogenesis; colorectal cancer; inflammation; microbiota.

Figure 1

A schematic diagram of the signaling pathways of microorganisms in the intestinal epithelium. Among them, NLR, TLR and RLR family members provide significant microbial signaling pathways in the intestinal epithelium. DAMPs and MAMPs on the epithelial barrier activate signaling pathways through different receptors. MAMPs activate muramyl dipeptide (MDP) and recognize NLRs. NOD1 and NOD2 are active in intestinal cells and can recognize caspase recruitment domains (card‐card). NOD1 and NOD2 interact with RIP2, stimulates TRAF6 and recognizes TAK1, triggers MAPK and NF‐κB. TLRs include TLR1, TLR2, and TLR4, which bind to MyD88 and activate NF‐κB by binding to IRAK1, 2, and 4. RLRs are capable of recognizing viral RNA, releasing IFN‐β, and activating NF‐κB. If the signal pathways are disrupted, inflammation may occur, leading to cancerous lesions.

Figure 2

Inflammation oncogenic signaling pathways. PAMPs recognize surface PRRs such as macrophages and dendritic cells. The inflammatory cells release cytokines such as IL‐6, IL‐23, TNF‐α et al. IL‐6 activates the NF‐κB and signal transducer and STAT3 pathways, which in turn induce cancer. IL‐17 is an important cytokine that also activates the NF‐κB and STAT3 signaling pathways, but requires the help of IL‐23. At the same time, the release of ROS and RNS, and chemical modifications such as methylation and amination, can damage DNA and promote the development of cancer.

Figure 3

The carcinogenic mechanisms of six major microorganisms. E. faecalis causes colitis after infection and expresses TGF‐β in intestinal epithelial cells, thereby activating SMAD4 signaling pathway. E. faecalis also produces extracellular superoxide and hydrogen peroxide,inducing DNA damage. Meanwhile, it also appears to be involved in the bystander effect of COX‐2, the endogenous CIN and cell transformation caused by the release of TNF‐α from macrophages, results in cancer. Some strains of E. coli B2 produce CDT and CNF, which can directly lead to a DNA damage response and genomic instability. At the same time, the mismatch repair pathway is inhibited, leading to tumorigenesis. E. coli can also induce late bridges and chromosomal aberrations by genomic toxin‐containing pks islands and catalyze the synthesis of colibactin by clbP. Eventually it leads to CIN, MSI and CIMP, which leads to cancer. ETBF synthesizes BFT. BFT binds to CECs and stimulates the cleavage of E‐cadherin, thereby amplifying the Wnt and NF‐κB pathway and releasing pro‐inflammatory mediators to destroy DNA. At the same time, ETBF activates the signal transducer and activator of STAT3 signaling pathway, induces the production of Th17, releases interleukin IL‐17, and promotes colon tumor formation. BFT rapidly causes the expression of SMO and promotes SMO‐dependent ROS production and damages DNA in intestinal epithelial cell lines. These reactions cause tumor formation. By complexing with E‐cadherin on epithelial cells, F. nucleatum stimulates FadA, which activates wnt/β‐catenin/TLR4/p‐PAK1 signaling and upregulates oncogene expression. By releasing RNA into host cells and activating NF‐κB, F. nucleatum stimulates inflammation. F. nucleatum also inhibits natural killer (NK) cell activity in the tumor microenvironment, leading to colorectal tumorigenesis. Helicobacter pylori causes the metastasis of colorectal cancer caused by chronic gastritis. In addition, H. pylori infection may cause colorectal epithelial damage through inflammatory reactions such as IL‐8 mediated inflammatory responses. H. pylori virulent strains induce enhanced inflammatory responses, and expression of the cytotoxin‐associated gene A (CagA) gene may also lead to colorectal cancer. The S. bovis antigen induces the expression of COX‐2. With the help of prostaglandins, COX‐2 promotes cell proliferation and angiogenesis, and inhibits apoptosis, thus stimulating the cancer pathway.