Natural products can be potential inhibitors of metalloproteinase II from Bacteroides fragilis to intervene colorectal cancer
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SUBMITTER: Arif B
PROVIDER: S-EPMC11239599 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:Bacteroides fragilis is a valuable anaerobic commensal and an essential component of the gut microbiome in humans. The presence of a short pathogenicity island in the genome is predominantly associated with the enterotoxigenic strains of B. fragilis. Metallopro-teinase II (MPII) and fragilysin (FRA) are the structurally related enzymes encoded by the pathogenicity island in the enterotoxigenic strains. Accordingly, there is a significant overlap between the cleavage preferences of MPII and FRA. These proteinases, however, are counter-transcribed in the bacterial genome suggesting their distinct and specialized functions in the course of infection. It is well established that FRA directly cleaves E-cadherin, a key protein of the cell-to-cell adhesion junctions in the intestinal epithelium. Counterintuitively, MPII directly binds to, rather than cleaves, E-cadherin. Structural modeling suggested that a potential E-cadherin binding site involves the C-terminal -helical region of the MPII catalytic domain. The sequence of this region is different in MPII and FRA. Here, we employed substitution mutagenesis of this C-terminal -helical region to isolate the MPII mutants with the potentially inactivated E-cadherin binding site. Overall, as a result of our modeling, mutagenesis and binding studies, we determined that the C-terminal ten residue segment is essential for the binding of MPII, but not of FRA3, to E-cadherin, and that the resulting MPII•E-cadherin complex does not impair E-cadherin-dependent cell-to-cell contacts. It is possible to envision that the putative cleavage targets of MPII should be explored not only on the host cell surface but also in B. fragilis.
| S-EPMC4425422 | biostudies-literature
Project description:To elucidate whether Enterotoxigenic Bacteroides fragilis (ETBF) plays a role in colorectal cancer tumorigenesis, a RNA-seq analysis was performed to compare the gene expression profiles of ETBF treated DLD-1 colorectal cancer cell lines.
2020-04-13 | GSE130152 | GEO
Project description:Enterotoxigenic anaerobic Bacteroides fragilis is a significant source of inflammatory diarrheal disease and a risk factor for colorectal cancer. Two distinct metalloproteinase types (the homologous 1, 2, and 3 isoforms of fragilysin (FRA1, FRA2, and FRA3, respectively) and metalloproteinase II (MPII)) are encoded by the B. fragilis pathogenicity island. FRA was demonstrated to be important to pathogenesis, whereas MPII, also a potential virulence protein, remained completely uncharacterized. Here, we, for the first time, extensively characterized MPII in comparison with FRA3, a representative of the FRA isoforms. We employed a series of multiplexed peptide cleavage assays to determine substrate specificity and proteolytic characteristics of MPII and FRA. These results enabled implementation of an efficient assay of MPII activity using a fluorescence-quenched peptide and contributed to structural evidence for the distinct substrate cleavage preferences of MPII and FRA. Our data imply that MPII specificity mimics the dibasic Arg↓Arg cleavage motif of furin-like proprotein convertases, whereas the cleavage motif of FRA (Pro-X-X-Leu-(Arg/Ala/Leu)↓) resembles that of human matrix metalloproteinases. To the best of our knowledge, MPII is the first zinc metalloproteinase with the dibasic cleavage preferences, suggesting a high level of versatility of metalloproteinase proteolysis. Based on these data, we now suggest that the combined (rather than individual) activity of MPII and FRA is required for the overall B. fragilis virulence in vivo.
| S-EPMC3843106 | biostudies-literature
Project description:BackgroundThe occurrence and development of colorectal cancer (CRC) is an incredibly long process that involves continuous changes in the tumor microenvironment. These constant changes may ultimately result in genetic alterations and changes in the metabolic processes of some symbiotic bacteria as a way to adapt to the changing environment. Patients with CRC exhibit an altered abundance of Bacteroides fragilis (B. fragilis) as indicated by several studies. To better understand the genomic characteristics and virulence spectrum of B. fragilis strains in tumor tissues, B. fragilis strains were isolated from tumor and paracancerous tissues of CRC patients.MethodsThe isolates were identified using 16 S rRNA sequencing, morphological analysis, physiological and biochemical characterization and PCR, and they were then subjected to whole genome sequencing (WGS) analysis.ResultsA strain of B. fragilis enterotoxin (BFT) bft1-producing ZY0302 and a non-enterotoxin-producing B. fragilis ZY0804 were isolated from cancerous and paraneoplastic tissues, respectively. Analysis based on the core and nonessential genes showed that the genomic profiles of the isolates, ZY0302 and ZY0804, differed from those of B. fragilis from other tissue sources. This core and the co-evolution of non-essential genes may be the result of their adaptation to fluctuations in the tumor microenvironment and enhancing their survival. In addition, the ZY0302 and ZY0804 genomes underwent extensive horizontal gene transfer and varying degrees of genomic rearrangements, inversions, insertions, and deletion events, which may favor the enhancement of bacteria's ability to adapt to environmental changes. For instance, the virulence factors, such as the capsular biosynthesis gene clusters and components of the type IV secretion system, acquired through horizontal gene transfer, may facilitated B. fragilis in evading immune responses and managing oxidative stress. Moreover, our analysis revealed that multiple virulence factors identified in the isolates were mainly involved in bacterial adhesion and colonization, oxidative stress, iron acquisition, and immune evasion. This observation is worth noting given that enzymes such as neuraminidase, lipase, hemolysin, protease, and phosphatase, along with genes responsible for LPS biosynthesis, which are recognized for their association with the virulence of B. fragilis, were prevalent among the isolates.ConclusionsIn summary, it is our assertion that the alterations observed in both core and nonessential genes of B. fragilis, which have been isolated from tissues of colorectal cancer patients, along with significant instances of horizontal gene transfer to the genome, are likely intended to enhance adaptation to the evolving conditions of the tumor microenvironment. This study may provide new insights into the interaction between B. fragilis and the CRC microenvironment.
| S-EPMC11921484 | biostudies-literature
Project description:BackgroundEnterotoxigenic Bacteroides fragilis (ETBF) is a toxin-producing bacteria thought to possibly promote colorectal carcinogenesis by modulating the mucosal immune response and inducing epithelial cell changes. Here, we aim to examine the association of colonic mucosal colonization with ETBF and the presence of a range of lesions on the colonic neoplastic spectrum.MethodsMucosal tissue from up to four different colonic sites was obtained from a consecutive series of 150 patients referred for colonoscopy. The presence and relative abundance of the B. fragilis toxin gene (bft) in each tissue sample was determined using quantitative PCR, and associations with clinicopathological characteristics were analysed.FindingsWe found a high concordance of ETBF between different colonic sites (86%). Univariate analysis showed statistically significant associations between ETBF positivity and the presence of low-grade dysplasia (LGD), tubular adenomas (TA), and serrated polyps (P-values of 0.007, 0.027, and 0.007, respectively). A higher relative abundance of ETBF was significantly associated with LGD and TA (P-values of < 0.0001 and 0.025, respectively). Increased ETBF positivity and abundance was also associated with left-sided biopsies, compared to those from the right side of the colon.ConclusionOur results showing association of ETBF positivity and increased abundance with early-stage carcinogenic lesions underlines its importance in the development of colorectal cancer, and we suggest that detection of ETBF may be a potential marker of early colorectal carcinogenesis.
| S-EPMC5289627 | biostudies-literature
Project description:BackgroundBacteroides fragilis is a part of the normal gastrointestinal flora, but it is also the most common anaerobic bacteria causing the infection. It is highly resistant to antibiotics and contains abundant antibiotic resistance mechanisms.MethodsThe antibiotic resistance pattern of 78 isolates of B. fragilis (22 strains from clinical samples and 56 strains from the colorectal tissue) was investigated using agar dilution method. The gene encoding Bacteroides fargilis toxin bft, and antibiotic resistance genes were targeted by PCR assay.ResultsThe highest rate of resistance was observed for penicillin G (100%) followed by tetracycline (74.4%), clindamycin (41%) and cefoxitin (38.5%). Only a single isolate showed resistance to imipenem which contained cfiA and IS1186 genes. All isolates were susceptible to metronidazole. Accordingly, tetQ (87.2%), cepA (73.1%) and ermF (64.1%) were the most abundant antibiotic-resistant genes identified in this study. MIC values for penicillin, cefoxitin and clindamycin were significantly different among isolates with the cepA, cfxA and ermF in compare with those lacking such genes. In addition, 22.7 and 17.8% of clinical and GIT isolates had the bft gene, respectively.ConclusionsThe finding of this study shows that metronidazole is highly in vitro active agent against all of B. fragilis isolates and remain the first-line antimicrobial for empirical therapy.
| S-EPMC8066845 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) is the third most diagnosed cancer and the second most common cause of cancer deaths worldwide. CRC patients present with an increase in pathogens in their gut microbiota, such as polyketide synthase-positive bacteria (pks +) and enterotoxigenic Bacteroides fragilis (ETBF). The pks + Escherichia coli promotes carcinogenesis and facilitates CRC progression through the production of colibactin, a genotoxin that induces double-strand DNA breaks (DSBs). ETBF is a procarcinogenic bacterium producing the B. fragilis toxin (bft) that promotes colorectal carcinogenesis by modulating the mucosal immune response and inducing epithelial cell changes.MethodsFecal samples were collected from healthy controls (N = 62) and CRC patients (N = 94) from the province of Québec (Canada), and a bacterial DNA extraction was performed. Fecal DNA samples were then examined for the presence of the pks island gene and bft using conventional qualitative PCR.ResultsWe found that a high proportion of healthy controls are colonized by pks + bacteria (42%) and that these levels were similar in CRC patients (46%). bft was detected in 21% of healthy controls and 32% of CRC patients, while double colonization by both pks + bacteria and ETBF occurred in 8% of the healthy controls and 13% of the CRC patients. Most importantly, we found that early-onset CRC (< 50 years) patients were significantly less colonized with pks + bacteria (20%) compared to late-onset CRC patients (52%).ConclusionsHealthy controls had similar levels of pks + bacteria and ETBF colonization as CRC patients, and their elevated levels may place both groups at greater risk of developing CRC. Colonization with pks + bacteria was less prevalent in early-compared to late-onset CRC.
| S-EPMC9798702 | biostudies-literature
Project description:Enterotoxigenic Bacteroides fragilis (ETBF) has received significant attention for a possible association with, or causal role in, colorectal cancer (CRC). The goal of this review was to assess the status of the published evidence supporting (i) the association between ETBF and CRC and (ii) the causal role of ETBF in CRC. PubMed and Scopus searches were performed in August 2021 to identify human, animal, and cell studies pertaining to the role of ETBF in CRC. Inclusion criteria included the use of cell lines, mice, exposure to BFT or ETBF, and detection of bft. Review studies were excluded, and studies were limited to the English language. Quality of study design and risk of bias analysis was performed on the cell, animal, and human studies using ToxRTools, SYRCLE, and NOS, respectively. Ninety-five eligible studies were identified, this included 22 human studies, 24 animal studies, 43 cell studies, and 6 studies that included both cells and mice studies. We found that a large majority of studies supported an association or causal role of ETBF in CRC, as well as high levels of study bias was detected in the in vitro and in vivo studies. The high-level heterogeneity in study design and reporting made it difficult to synthesize these findings into a unified conclusion, suggesting that the need for future studies that include improved mechanistic models, longitudinal in vitro and in vivo evidence, and appropriate control of confounding factors will be required to confirm whether ETBF has a direct role in CRC etiopathogenesis.
| S-EPMC9046963 | biostudies-literature
Project description:BackgroundEnterotoxigenic Bacteroides fragilis (ETBF) has been implicated in colorectal carcinogenesis through the actions of its toxin, B. fragilis toxin (BFT). Studies on colorectal cell lines have shown that treatment with BFT causes disruption of E-cadherin leading to increased expression of the pro-inflammatory cytokine, IL-8. Stat3 activation has also been associated with ETBF-related colitis and tumour development. However, a link between E-cadherin, IL-8 and Stat3 has not been investigated in the context of ETBF infection.ResultsWe found that co-culture of HT-29 and HCT116 colorectal cell lines with ETBF, had a similar effect on activation of IL8 gene and protein expression as treatment with purified BFT. Inhibition of Stat3 resulted in a decrease in IL-8 gene and protein expression in response to ETBF in both cell lines. A reduction in E-cadherin expression in response to ETBF treatment was not restored by blocking Stat3.ConclusionWe found that treatment of colorectal cancer cell lines with live cultures of ETBF had the equivalent effect on IL-8 expression as the use of purified toxin, and this may be a more representative model of ETBF-mediated colorectal carcinogenesis. IL-8 gene and protein expression was mediated through Stat3 in HT-29 and HCT116 cells, whereas disruption of E-cadherin appeared to be independent of Stat3 signalling.
| S-EPMC9036718 | biostudies-literature
Project description:The idea was to examine the role of OxyR in control of the oxidative stress response of B. fragilis when exposed to either atmospheric oxygen, 5% oxygen atmosphere, or hydrogen peroxide Keywords: stress response
2007-12-30 | GSE4583 | GEO