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Cynthia L Sears - One of the best experts on this subject based on the ideXlab platform.
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epigenetic changes induced by Bacteroides fragilis toxin
Infection and Immunity, 2019Co-Authors: Jawara Allen, Cynthia L Sears, Stephanie Hao, Winston TimpAbstract:Enterotoxigenic Bacteroides fragilis (ETBF) is a gram negative, obligate anaerobe member of the gut microbial community in up to 40% of healthy individuals. This bacterium is found more frequently in people with colorectal cancer (CRC) and causes tumor formation in the distal colon of Apc min/+ mice; tumor formation is dependent on ETBF-secreted Bacteroides fragilis toxin (BFT). Because of the extensive data connecting alterations in the epigenome with tumor formation, initial experiments attempting to connect BFT-induced tumor formation with methylation in colon epithelial cells (CECs) have been performed, but the effect of BFT on other epigenetic processes, such as chromatin structure, remains unexplored. Here, the changes in gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) induced by treatment of HT29/C1 cells with BFT for 24 and 48 hours is examined. Our data show that several genes are differentially expressed after BFT treatment and these changes relate to the interaction between bacteria and CECs. Further, sites of increased chromatin accessibility are associated with the location of enhancers in CECs and binding sites of transcription factors in the AP-1/ATF family; they are also enriched for common differentially methylated regions (DMRs) in CRC. These data provide insight into the mechanisms by which BFT induces tumor formation and lay the groundwork for future in vivo studies to explore the impact of BFT on nuclear structure and function.
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epigenetic changes induced by Bacteroides fragilis toxin
bioRxiv, 2018Co-Authors: Jawara Allen, Cynthia L Sears, Stephanie Hao, Winston TimpAbstract:Enterotoxigenic Bacteroides fragilis (ETBF) is a gram negative, obligate anaerobe member of the gut microbial community in up to 40% of healthy individuals. This bacterium is found more frequently in people with colorectal cancer (CRC) and causes tumor formation in the distal colon of mice heterozygous for the adenomatous polyposis coli gene ( Apc +/- ); tumor formation is dependent on ETBF-secreted Bacteroides fragilis toxin (BFT). Though some of the immediate downstream effects of BFT on colon epithelial cells (CECs) are known, we still do not understand how this potent exotoxin causes changes in CECs that lead to tumor formation and growth. Because of the extensive data connecting alterations in the epigenome with tumor formation, initial experiments attempting to connect BFT-induced tumor formation with methylation in CECs have been performed, but the effect of BFT on other epigenetic processes, such as chromatin structure, remains unexplored. Here, the changes in chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) induced by treatment of HT29/C1 cells with BFT for 24 and 48 hours is examined. Our data show that several genes are differentially expressed after BFT treatment and these changes correlate with changes in chromatin accessibility. Also, sites of increased chromatin accessibility are associated with a lower frequency of common single nucleotide variants (SNVs) in CRC and with a higher frequency of common differentially methylated regions (DMRs) in CRC. These data provide insight into the mechanisms by which BFT induces tumor formation. Further understanding of how BFT impacts nuclear structure and function in vivo is needed.
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Bacteroides fragilis subverts mucosal biology from symbiont to colon carcinogenesis
Journal of Clinical Investigation, 2014Co-Authors: Cynthia L Sears, Abby L Geis, Franck HousseauAbstract:The human body comprises fewer host cells than bacterial cells, most of which are obligate anaerobes residing in the gut. The symbiont Bacteroides fragilis constitutes a relatively small proportion (up to 1%–2%) of cultured fecal bacteria, but colonizes most humans. There are 2 classes of B. fragilis distinguished by their ability to secrete a zinc-dependent metalloprotease toxin, B. fragilis toxin (BFT). Strains that do not secrete BFT are nontoxigenic B. fragilis (NTBF), and those that do are called enterotoxigenic B. fragilis (ETBF). ETBF can induce clinical pathology, including inflammatory diarrhea, although asymptomatic colonization may be common. Intestinal inflammation is mediated by BFT, as yet the only known virulence factor of ETBF. Recent experimental evidence demonstrating that ETBF-driven colitis promotes colon tumorigenesis has generated interest in the potential contribution of ETBF to human colon carcinogenesis. Critical questions about the epidemiology of chronic, subclinical human colonization with ETBF and its impact on the biology of the colon need to be addressed.
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polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis induced colon tumorigenesis
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Andrew C Goodwin, Cynthia L Sears, Christina Destefano E Shields, David L Huso, Shervin Rabizadeh, Tracy Murraystewart, Amy Hackerprietz, Patrick M Woster, Robert A CaseroAbstract: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) up-regulates 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.
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enterotoxigenic Bacteroides fragilis a rogue among symbiotes
Clinical Microbiology Reviews, 2009Co-Authors: Cynthia L SearsAbstract:Summary: Enterotoxigenic Bacteroides fragilis (ETBF) strains are strains of B. fragilis that secrete a 20-kDa heat-labile zinc-dependent metalloprotease toxin termed the B. fragilis toxin (BFT). BFT is the only recognized virulence factor specific for ETBF. ETBF strains are associated with inflammatory diarrheal disease in children older than 1 year of age and in adults; limited data suggest an association of ETBF colonization with inflammatory bowel disease flare-ups and colorectal cancer. ETBF secretes one of three highly related BFT isoforms. The relationship between BFT isoform and disease expression is unknown. Although the mechanism of action of BFT is incompletely understood, available data suggest that BFT binds to a specific intestinal epithelial cell receptor, stimulating intestinal cell signal transduction pathways that result in cell morphology changes, cleavage of E-cadherin, reduced colonic barrier function, and increased epithelial cell proliferation and cytokine expression (such as the proinflammatory chemokine interleukin-8). Together, the data suggest that in some hosts, ETBF acts via secretion of BFT to induce colitis. However, the full spectrum of clinical disease related to ETBF and the impact of chronic ETBF colonization on the host remain to be defined.
Dennis L. Kasper - One of the best experts on this subject based on the ideXlab platform.
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beneficial bacteria that affect toll like receptors in the gut immune system the case of psa on Bacteroides fragilis and transcription profile of developmentally regulated genes
Nobel Day 10th Conference School of Medical Sceinces Örebro University 10 December 2018, 2018Co-Authors: Frida Gorreja, Dennis L. Kasper, Stephen Rush, R J M Brummer, Di Meng, Allan W WalkerAbstract:Beneficial bacteria that affect Toll-like receptors in the gut immune system : the case of PSA on Bacteroides fragilis and transcription profile of developmentally-regulated genes
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BRIEF COMMUNICATIONS Bacteroides fragilis Subspecies in Clinical Isolates
2016Co-Authors: Dennis L. KasperAbstract:Isolates of Bacteroides fragilis from 83 infected patients were collected during 2 years. Of 103 isolates, 6 8 % were subspecies fragilis. This was the single most common subspecies isolated from blood (12/17), intra-abdominal (11/28) , wound (17/20), perirectal (11/16) , pelvic (6/10), and other (8/11) sites. Sixteen patients had B. fragilis isolated in pure culture. Of these, 9 /12 blood cultures and 4 / 4 cultures from other sites were ss. fragilis. The recent observation that ss. fragilis organisms are encapsulated whereas the other subspecies are generally unencapsulated was supported by indirect fluorescent antibody studies using antibodies prepared to the capsular material of ss. fragilis. All 33 strains of ss. fragilis and none of 13 strains of other subspecies were positive. The predominance of ss. fragilis in clinical isolates compared to its relative infrequency in normal fecal flora and its predominance in pure cultures, especially of blood, indicate that this is the most virulent of B. fragilis subspecies. This virulence may be related to encapsulation. IMPROVEMENTS IN LABORATORY METHODS and clarification of taxonomy have resulted in an increased awareness of the prevalence and virulence of anaerobic Gram-negative, non-spore-forming bacilli in clinical infections. Bacteroides fragilis is the single most common anaerobic organism found in clinical specimens (1). B. fragilis has been di-vided into five subspecies, as well as a group called "other" by Holdeman and Moore (2). These known subspecies are ss. fragilis, ss. thetaiotaomicron, ss. distasonis, ss. vulgatus, and ss. ovatus. Other investigators have reported in the microbiology literature that ss. fragilis is the subspecies most frequently isolated from clinical material (3, 4). Kasper and associates (5) have observed that ss. fragilis organisms are encapsulated whereas those of other sub-species are generally not. During a 2-year period, we subspeciated all clinical isolates of B. fragilis identified in the clinical microbiology laboratory at Boston City Hos-pital, and reviewed the patients ' records to define more clearly the clinical implications of the subspecies
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Bacteroides fragilis polysaccharide a is necessary and sufficient for acute activation of intestinal sensory neurons
Nature Communications, 2013Co-Authors: Yukang Mao, Dennis L. Kasper, Bingxian Wang, Paul Forsythe, John Bienenstock, Wolfgang KunzeAbstract:Symbionts or probiotics are known to affect the nervous system. To understand the mechanisms involved, it is important to measure sensory neuron responses and identify molecules responsible for this interaction. Here we test the effects of adding Lactobacillus rhamnosus (JB-1) and Bacteroides fragilis to the epithelium while making voltage recordings from intestinal primary afferent neurons. Sensory responses are recorded within 8 s of applying JB-1 and excitability facilitated within 15 min. Bacteroides fragilis produces similar results, as does its isolated, capsular exopolysaccharide, polysaccharide A. Lipopolysaccharide-free polysaccharide A completely mimics the neuronal effects of the parent organism. Experiments with a mutant Bacteroides fragilis devoid of polysaccharide A shows that polysaccharide A is necessary and sufficient for the neuronal effects. Complex carbohydrates have not been reported before as candidates for such signalling between symbionts and the host. These observations indicate new neuronal targets and invite further study of bacterial carbohydrates as inter-kingdom signalling molecules between beneficial bacteria and sensory neurons.
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orientations of the Bacteroides fragilis capsular polysaccharide biosynthesis locus promoters during symbiosis and infection
Journal of Bacteriology, 2010Co-Authors: Erin B Troy, Dennis L. Kasper, Vincent J Carey, Laurie E ComstockAbstract:Orientations of the seven invertible polysaccharide biosynthesis locus promoters of Bacteroides fragilis were determined from bacteria grown in vitro, from feces of monoassociated and complex colonized mice, and from B. fragilis-induced murine abscesses. Bacteria grown in vivo have greater variability in orientation of polysaccharide locus promoters than culture-grown organisms.
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a polysaccharide from the human commensal Bacteroides fragilis protects against cns demyelinating disease
Mucosal Immunology, 2010Co-Authors: Javier Ochoareparaz, Dennis L. Kasper, Daniel Mielcarz, Yan Wang, Sakhina Begumhaque, Suryasarathi Dasgupta, Lloyd H KasperAbstract:The intestinal microbiome may have a critical roll in susceptibility or resistance to immune-mediated diseases. Alterations of the gut microflora after oral antibiotic treatment can regulate encephalomyelitis (EAE), an animal model for human multiple sclerosis (MS). We now show that a zwitterionic capsular polysaccharide A (PSA) of Bacteroides fragilis can protect against central nervous system demyelinating disease. Oral administration with purified PSA protected mice against EAE prophylactic and therapeutically. PSA treatment enhanced CD103 expressing dendritic cells (DCs) that accumulated in the cervical lymph nodes. Exposure of naive DCs to PSA induced the conversion of naive CD4(+) T cells into interleukin (IL)-10-producing FoxP3(+)Treg cells. Protection against EAE was completely abrogated in IL-10-deficient mice. Our results show an important role for a molecule from human commensal bacteria in protecting against EAE and suggest the possibility for protection in MS.
K D Allen - One of the best experts on this subject based on the ideXlab platform.
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metronidazole resistant Bacteroides fragilis wound infection
Journal of Infection, 1992Co-Authors: M A T Odonoghue, J Potter, K D AllenAbstract:Summary We report the isolation of metronidazole-resistant Bacteroides fragilis from a postoperative wound abscess in a 72-year-old woman who had not been treated with metronidazole during the preceding 9 months. The case illustrates the need for caution when identifying anaerobes on the basis of metronidazole sensitivity.
Ajit P Limaye - One of the best experts on this subject based on the ideXlab platform.
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isolation of metronidazole resistant Bacteroides fragilis carrying the nima nitroreductase gene from a patient in washington state
Journal of Clinical Microbiology, 2004Co-Authors: Jeffrey M Schapiro, Rachna Gupta, Eric Stefansson, Ferric C Fang, Ajit P LimayeAbstract:Members of the Bacteroides fragilis group are among the most common anaerobic bacterial isolates in clinical specimens. Metronidazole, a 5-nitroimidazole, is often used as empirical therapy for anaerobic infections. Susceptibility testing is not routinely performed because of nearly universal susceptibility of Bacteroides spp. to this agent. We report a case of metronidazole-resistant Bacteroides fragilis in the United States and demonstrate the presence of the nimA gene, encoding a nitroreductase previously shown to mediate resistance to 5-nitroimidazole antimicrobial agents in B. fragilis strains from Europe and Africa. Because clinical failures in Bacteroides infections have been associated with the use of inactive antimicrobial agents, clinicians need to be aware of the possibility of metronidazole-resistant B. fragilis strains in the United States and the importance of susceptibility testing in selected situations.
Ki Jong Rhee - One of the best experts on this subject based on the ideXlab platform.
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enterotoxigenic Bacteroides fragilis infection exacerbates tumorigenesis in aom dss mouse model
International Journal of Medical Sciences, 2020Co-Authors: Soonjae Hwang, Chang Gun Lee, Chan Oh Park, Sun Yeong Gwon, Samnoh Hwang, Soyeon Lee, Yongbin Eom, Baktiar Karim, Ki Jong RheeAbstract:The azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model is commonly used to study colitis-associated cancer. The human commensal bacterium, enterotoxigenic Bacteroides fragilis (ETBF) secretes the Bacteroides fragilis toxin (BFT) which is necessary and sufficient to cause colitis. We report that BALB/c mice infected with WT-ETBF and administered three cycles of AOM/DSS developed numerous, large-sized polyps predominantly in the colorectal region. In addition, AOM/DSS-treated BALB/c mice orally inoculated with wild-type nontoxigenic Bacteroides fragilis (WT-NTBF) overexpressing bft (rETBF) developed numerous polyps whereas mice infected with WT-NTBF overexpressing a biologically inactive bft (rNTBF) did not promote polyp formation. Unexpectedly, the combination of AOM+ETBF did not induce polyp formation whereas ETBF+DSS did induce polyp development in a subset of BALB/c mice. In conclusion, WT-ETBF promoted polyp development in AOM/DSS murine model with increased colitis in BALB/c mice. The model described herein provides an experimental platform for understanding ETBF-induced colonic tumorigenesis and studying colorectal cancer in wild-type mice.
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zerumbone suppresses enterotoxigenic Bacteroides fragilis infection induced colonic inflammation through inhibition of nf κβ
International Journal of Molecular Sciences, 2019Co-Authors: Soonjae Hwang, Chang Gun Lee, Chan Oh Park, Ju Eun Hong, Miyong Yun, Ki Jong RheeAbstract:Enterotoxigenic Bacteroides fragilis (ETBF) is human intestinal commensal bacterium and a potent initiator of colitis through secretion of the metalloprotease Bacteroides fragilis toxin (BFT). BFT induces cleavage of E-cadherin in colon cells, which subsequently leads to NF-κB activation. Zerumbone is a key component of the Zingiber zerumbet (L.) Smith plant and can exhibit anti-bacterial and anti-inflammatory effects. However, whether zerumbone has anti-inflammatory effects in ETBF-induced colitis remains unknown. The aim of this study was to determine the anti-inflammatory effect of orally administered zerumbone in a murine model of ETBF infection. Wild-type C57BL/6 mice were infected with ETBF and orally administered zerumbone (30 or 60 mg/kg) once a day for 7 days. Treatment of ETBF-infected mice with zerumbone prevented weight loss and splenomegaly and reduced colonic inflammation with decreased macrophage infiltration. Zerumbone treatment significantly decreased expression of IL-17A, TNF-α, KC, and inducible nitric oxide synthase (iNOS) in colonic tissues of ETBF-infected mice. In addition, serum levels of KC and nitrite was also diminished. Zerumbone-treated ETBF-infected mice also showed decreased NF-κB signaling in the colon. HT29/C1 colonic epithelial cells treated with zerumbone suppressed BFT-induced NF-κB signaling and IL-8 secretion. However, BFT-mediated E-cadherin cleavage was unaffected. Furthermore, zerumbone did not affect ETBF colonization in mice. In conclusion, zerumbone decreased ETBF-induced colitis through inhibition of NF-κB signaling.
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induction of persistent colitis by a human commensal enterotoxigenic Bacteroides fragilis in wild type c57bl 6 mice
Infection and Immunity, 2009Co-Authors: Ki Jong Rhee, David L Huso, Baktiar O Karim, Augusto A Franco, Shervin Rabizadeh, Jonathan E Golub, Lauren E Mathews, Jai Shin, Balfour R Sartor, Douglas T GolenbockAbstract:Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.
