Three specific gut bacteria in the occurrence and development of colorectal cancer: a concerted effort

Abstract

Colorectal cancer (CRC), which develops from the gradual evolution of tubular adenomas and serrated polyps in the colon and rectum, has a poor prognosis and a high mortality rate. In addition to genetics, lifestyle, and chronic diseases, intestinal integrity and microbiota (which facilitate digestion, metabolism, and immune regulation) could promote CRC development. For example, enterotoxigenic Bacteroides fragilis, genotoxic Escherichia coli (pks+ E. coli), and Fusobacterium nucleatum, members of the intestinal microbiota, are highly correlated in CRC. This review describes the roles and mechanisms of these three bacteria in CRC development. Their interaction during CRC initiation and progression has also been proposed. Our view is that in the precancerous stage of colorectal cancer, ETBF causes inflammation, leading to potential changes in intestinal ecology that may provide the basic conditions for pks+ E. coli colonization and induction of oncogenic mutations, when cancerous intestinal epithelial cells can further recruit F. nucleatum to colonise the lesion site and F. nucleatum may contribute to CRC advancement by primarily the development of cancer cells, stemization, and proliferation, which could create new and tailored preventive, screening and therapeutic interventions. However, there is the most dominant microbiota in each stage of CRC development, not neglecting the possibility that two or even all three bacteria could be engaged at any stage of the disease. The relationship between the associated gut microbiota and CRC development may provide important information for therapeutic strategies to assess the potential use of the associated gut microbiota in CRC studies, antibiotic therapy, and prevention strategies.

Keywords: Enterotoxigenic Bacteroides fragilis; Fusobacterium nucleatum; Genotoxic Escherichia coli; Gut microbiota.

Figure 1. The role and mechanism of ETBF in the pathogenesis of CRC.

(A) Activation of the Wnt/β-catenin pathway by BFT. When BFT-r on the surface of colonic epithelial cells (CECs) is exposed to (and binds to) BFT toxin, the extracellular structure of E-cadherin cleaves, falls off and is degraded completely. As the structure of E-cadherin changes, β-catenin, which is bound to its intracellular domain dissociates. The abnormally expressed β-catenin escapes the regulation of APC protein and enters the nucleus to form a complex with TCF4. This leads to c-Myc activation. Eventually, the CECs become cancerous. (B) Inflammatory cascade activation by BFT. Colonic epithelial cells (CECs), neutrophils, and Th17 cells interact during BFT-induced inflammation. Invasion of CECs by ETBF results in IL-8 release for the recruitment of neutrophils. IL-6 released from the neutrophils activates the JAK/STAT3 signaling pathway in Th17 cells and CECs, via binding to IL-6-r. IL-17 secreted from mobilised TH17 cells plays autocrine and paracrine roles by binding to IL-17-r, resultings in the activation of the NF-κB pathway in CECs and IL-6 as well. (C) The role of BFT at the tumorigenesis stage. Following BFT-induced overexpression of lncRNA-BFAL1, the later binds to miR-155-5p and miR-200a-3p to activate the mTORC1 pathway, which promotes further tumor growth. Activation of TLR4 by BFT leads to NFAT5 activation, upregulation of JMJD2B and demethylation of H3K9me3. Upregulation of NANOG and stemness of CRC cells are finally enhanced.

Figure 2. The role and mechanism of pks+ E. coli in the pathogenesis of CRC.

Mutations in single bases and CIN are based on the “contribution” of E. coli toxins, which exhibit a “hit and run” mechanism. E. coli genotoxin induces miR-20a-5p expression via c-Myc (a transcription factor), and up-regulates the expression of miR-20a-5p (bound to SENP1) leading to the latter’s translational silencing, and thus P53 SUMOylation. P53 SUMOylation leads to up-regulation of HGF phosphorylation of HGF-r and inactivation of miR-34, which promote tumor growth.

Figure 3. Adhesion and invasion of vascular endothelial cells by F. nucleatum.

F. nucleatum invades vascular endothelial cells through the binding of FadA to its vascular endothelial cell surface receptor CDH5 (a member of the cadherin superfamily). Binding of FadA causes CDH5 to relocate and increases endothelial permeability, thereby promoting Clostridium perfringens and infiltration into the bloodstream.

Figure 4. The role and mechanism of F. nucleatum in the pathogenesis of CRC.

F. nucleatum is recruited to colon tumor site by the binding of Fap2 to Gal-GalNAc, which is overexpressed in CRC. FadA (an F. nucleatum virulence factor) binds to E-cadherin to activate Wnt/ß-catenin signalling, leading to tumor development and CRC cell proliferation. Activation of immune cells such as NK and T cells is inhibited by specific binding of the adhesion protein Fap2 to hTIGIT. The expression of ENO1, via the transcription factor SP1 (regulated by F. nucleatum), leads to increased glycolysis.

Figure 5. Hypothesised cooperative relationship between ETBF, pks+ E. coli, and F. nucleatum.

During the precancerous stage of CRC, ETBF causes inflammation and this could lead to an imbalance in the ecological niche. This potential change in the intestinal ecology could provide the basic conditions for pks+ E. coli colonisation and the induction of genetic mutations in the carcinogenesis stage. Under the influence of E. coli, cancerous intestinal epithelial cells could further recruit F. nucleatum to colonise the lesion site. F. nucleatum may contribute to CRC advancement by primarily the development of cancer cells, stemization, and proliferation.