The Mechanism of Bacteroides fragilis Toxin Contributes to Colon Cancer Formation

Abstract

The Bacteroides fragilis ( B. fragilis ) produce biofilm for colonisation in the intestinal tract can cause a series of inflammatory reactions due to B. fragilis toxin (BFT) which can lead to chronic intestinal inflammation and tissue injury and play a crucial role leading to colorectal cancer (CRC). The enterotoxigenic B. fragilis (ETBF) forms biofilm and produce toxin and play a role in CRC, whereas the non-toxigenic B. fragilis (NTBF) does not produce toxin. The ETBF triggers the expression of cyclooxygenase (COX)-2 that releases PGE2 for inducing inflammation and control cell proliferation. From chronic intestinal inflammation to cancer development, it involves signal transducers and activators of transcription (STAT)3 activation. STAT3 activates by the interaction between epithelial cells and BFT. Thus, regulatory T-cell (Tregs) will activates and reduce interleukin (IL)-2 amount. As the level of IL-2 drops, T-helper (T h 17) cells are generated leading to increase in IL-17 levels. IL-17 is implicated in early intestinal inflammation and promotes cancer cell survival and proliferation and consequently triggers IL-6 production that activate STAT3 pathway. Additionally, BFT degrades E-cadherin, hence alteration of signalling pathways can upregulate spermine oxidase leading to cell morphology and promote carcinogenesis and irreversible DNA damage. Patient with familial adenomatous polyposis (FAP) disease displays a high level of tumour load in the colon. This disease is caused by germline mutation of the adenomatous polyposis coli ( APC ) gene that increases bacterial adherence to the mucosa layer. Mutated- APC gene genotype with ETBF increases the chances of CRC development. Therefore, the colonisation of the ETBF in the intestinal tract depicts tumour aetiology can result in risk of hostility and effect on human health.

Gut Microbiota and Colorectal Cancer Development: A Closer Look to the Adenoma-Carcinoma Sequence

“…Over-expression of proinflammatory cytokines, such as IL-12, IL-23, IFNγ and TNF-α by dendritic cells, macrophages, and natural killer (NK) cells, may further promote the activation of T and B cells and different inflammatory mediators. The activation of signaling pathways by transcription factors such as NF-κB and signal transducer and activator of transcription 3 (STAT3) in colonic epithelial cells, the production of reactive oxygen species (ROS) and the related oxidative stress, DNA damage, and abnormal cell proliferation, may favor the development of colorectal adenomas and cancer [ 70 , 71 , 72 ] ( Figure 1 ).…”

YYFZBJS Inhibits Colorectal Tumorigenesis by Remodeling Enterotoxigenic Bacteroides Fragilis Mediated M2 Macrophage Polarization in Vivo and in Vitro

“…To our knowledge, the enterotoxigenic B. fragilis (ETBF) forms bio lm and produce toxin and play a role in CRC, whereas the non-toxigenic B. fragilis (NTBF) does not produce toxin. ETBF is associated with IBD due to the abnormal regulation of immune response to bacteria [41]. Pathogenic bacteria are capable of stimulating infection, in ammation and carcinogenesis, whereas the relationship between IBD and CRC is well established [42].…”

Role of Bacteria in the Incidence of Common GIT Cancers: The Dialectical Role of Integrated Bacterial DNA in Human Carcinogenesis

“…B. fragilis is classified according to toxin production into two types; the first type is non-toxigenic B. fragilis (NTBF), while the second type is enterotoxigenic B. fragilis (ETBF) which constitutively produce B. fragilis toxin (BFT) that is encoded by a chromosomal gene known as B. fragilis toxin ( bft ) gene. 38 …”

“…It has been proven that chronic inflammation and tissue injury enhance and accelerate the process of carcinogenesis. 38–41 …”

“…B. fragilis is classified according to toxin production into two types; the first type is non-toxigenic B. fragilis (NTBF), while the second type is enterotoxigenic B. fragilis (ETBF) which constitutively produce B. fragilis toxin (BFT) that is encoded by a chromosomal gene known as B. fragilis toxin (bft) gene. 38 Fragilysin, or the so-called BFT, is a 20-kDa zincdependent metalloproteinase toxin which involved in colon carcinogensis through biofilm formation and intestinal inflammation that damages the tight junction of the intestinal epithelium, leading to increased intestinal permeability. It has been proven that chronic inflammation and tissue injury enhance and accelerate the process of carcinogenesis.…”