Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Abstract

It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer

“…In addition, patients with IBD were recently demonstrated to have a reduced abundance of some members of the gut microbiota, including Firmicutes and Bacteroidetes (16,17). Streptoccus bovis/ gallolyticus, enterotoxigenic Bacterodies fragillis, and Escherichia coli NC101 have been implicated as risk factors for CRC (18)(19)(20). Furthermore, spontaneous intestinal auto-inflammation in several murine models fails to develop in the germ-free setting (21).…”

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“…In the genesis of colon cancer, at least in the 2% cases induced by a pre-existing inflammatory colitis, several studies demonstrated that microbiota can influence inflammation or innate immunity, genomic stability of intestinal epithelial cells (IECs) or the release of metabolites functioning as histone deacetylase (HDAC) inhibitors to regulate epigenetically host gene expression. [22][23][24][25][26][27][28][29][30][31][32][33][34] Integrating all the current data, Tjalsma et al 35 proposed a bacterial driver-passenger model for microbial involvement in the development of colorectal cancer, implying that bacteria must be incorporated into the genetic paradigm of cancer progression. According to this model, distinct indigenous intestinal bacteria, the 'driver bacteria' would create DNA damage and drive genome instability to initiate the first steps of tumorigenesis.…”

Certaines bactéries de la flore commensale exacerberaient-elles la carcinogenèse colorectale ?

“…La fragilysine pourrait aussi participer acti vement aux anomalies génétiques des cellules tumorales. En effet, in vivo, cette toxine induit au niveau des cellules épithéliales coliques, des dommages à l'ADN, ce qui pourrait conduire à l'accumulation de mutations [13].…”