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  1. Article ; Online: Liberation of host heme by Clostridioides difficile-mediated damage enhances Enterococcus faecalis fitness during infection

    Alexander B. Smith / Jonathan T. Specker / Katharine K. Hewlett / Troy R. Scoggins / Montana Knight / Abigail M. Lustig / Yanhong Li / Kirsten M. Evans / Yingchan Guo / Qianxuan She / Michael W. Christopher / Timothy J. Garrett / Ahmed M. Moustafa / Daria Van Tyne / Boone M. Prentice / Joseph P. Zackular

    mBio, Vol 15, Iss

    2024  Volume 1

    Abstract: ABSTRACTToxin production by Clostridioides difficile damages the colonic epithelium and leads to a robust inflammatory response. This disruption of the epithelial barrier markedly alters the nutritional landscape in the C. difficile-infected gut. The ... ...

    Abstract ABSTRACTToxin production by Clostridioides difficile damages the colonic epithelium and leads to a robust inflammatory response. This disruption of the epithelial barrier markedly alters the nutritional landscape in the C. difficile-infected gut. The impact of toxin-mediated nutritional remodeling during C. difficile infection (CDI) on resident microbiota remains largely unexplored. One group of opportunistic pathogens, the enterococci, thrive during CDI, but it is unclear what strategies they employ to survive in this altered environment. Here, we demonstrate that Enterococcus faecalis, a heme auxotroph, takes advantage of C. difficile toxin-mediated damage to acquire host heme for enhanced fitness. Specifically, heme acquired from the C. difficile-infected gut is used by E. faecalis to populate a heme-dependent cytochrome and aerobically respire. This fitness advantage is specific to C. difficile toxin-mediated damage, as infection with a toxin-null strain of C. difficile does not provide E. faecalis with a fitness advantage. Finally, targeted disruption of the E. faecalis cytochrome (cydABDC) operon leads to a fitness defect in the C. difficile-infected gut. Together, this work demonstrates that C. difficile toxin remodels the gut ecosystem and improves the fitness of E. faecalis in a cydABDC-dependent manner. These data further highlight growing evidence of a cooperative partnership between C. difficile and enterococci that has implications on susceptibility to and severity of CDI.IMPORTANCEClostridioides difficile and Enterococcus faecalis are two pathogens of great public health importance. Both bacteria colonize the human gastrointestinal tract where they are known to interact in ways that worsen disease outcomes. We show that the damage associated with C. difficile infection (CDI) releases nutrients that benefit E. faecalis. One particular nutrient, heme, allows E. faecalis to use oxygen to generate energy and grow better in the gut. Understanding the mechanisms of these interspecies interactions could ...
    Keywords Clostridioides difficile ; Enterococcus ; heme ; infectious disease ; gut microbiome ; microbial ecology ; Microbiology ; QR1-502
    Subject code 612
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher American Society for Microbiology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis

    Joseph P. Zackular / Nielson T. Baxter / Grace Y. Chen / Patrick D. Schloss

    mSphere, Vol 1, Iss

    2016  Volume 1

    Abstract: ABSTRACT There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor- ... ...

    Abstract ABSTRACT There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. In addition, it is likely that the loss of key bacterial populations may result in the loss of protective functions that are normally provided by the microbiota. We explored the role of the gut microbiota in colon tumorigenesis by using an inflammation-based murine model. We observed that perturbing the microbiota with different combinations of antibiotics reduced the number of tumors at the end of the model. Using the random forest machine learning algorithm, we successfully modeled the number of tumors that developed over the course of the model on the basis of the initial composition of the microbiota. The timing of antibiotic treatment was an important determinant of tumor outcome, as colon tumorigenesis was arrested by the use of antibiotics during the early inflammation period of the murine model. Together, these results indicate that it is possible to predict colon tumorigenesis on the basis of the composition of the microbiota and that altering the gut microbiota can alter the course of tumorigenesis. IMPORTANCE Mounting evidence indicates that alterations to the gut microbiota, the complex community of bacteria that inhabits the gastrointestinal tract, are strongly associated with the development of colorectal cancer. We used antibiotic perturbations to a murine model of inflammation-driven colon cancer to generate eight starting communities that resulted in various severities of tumorigenesis. Furthermore, we were able to quantitatively predict the final number of tumors on the basis of the initial composition of the gut microbiota. These results further bolster the evidence that the gut microbiota is involved in mediating the development of colorectal cancer. As a final proof of principle, we showed that perturbing the gut microbiota in the midst of tumorigenesis could halt the formation of additional tumors. Together, alteration of the gut microbiota may be a useful therapeutic approach to preventing and altering the trajectory of colorectal cancer.
    Keywords 16S rRNA gene sequencing ; azoxymethane ; colorectal cancer ; dextran sodium sulfate ; microbial ecology ; microbiome ; Microbiology ; QR1-502
    Subject code 616
    Language English
    Publishing date 2016-02-01T00:00:00Z
    Publisher American Society for Microbiology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Heme sensing and detoxification by HatRT contributes to pathogenesis during Clostridium difficile infection.

    Reece J Knippel / Joseph P Zackular / Jessica L Moore / Arianna I Celis / Andy Weiss / M Kay Washington / Jennifer L DuBois / Richard M Caprioli / Eric P Skaar

    PLoS Pathogens, Vol 14, Iss 12, p e

    2018  Volume 1007486

    Abstract: Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing symptoms ranging from infectious diarrhea to fulminant colitis. In the last decade, the number of C. difficile infections has dramatically risen, ... ...

    Abstract Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing symptoms ranging from infectious diarrhea to fulminant colitis. In the last decade, the number of C. difficile infections has dramatically risen, making it the leading cause of reported hospital acquired infection in the United States. Bacterial toxins produced during C. difficile infection (CDI) damage host epithelial cells, releasing erythrocytes and heme into the gastrointestinal lumen. The reactive nature of heme can lead to toxicity through membrane disruption, membrane protein and lipid oxidation, and DNA damage. Here we demonstrate that C. difficile detoxifies excess heme to achieve full virulence within the gastrointestinal lumen during infection, and that this detoxification occurs through the heme-responsive expression of the heme activated transporter system (HatRT). Heme-dependent transcriptional activation of hatRT was discovered through an RNA-sequencing analysis of C. difficile grown in the presence of a sub-toxic concentration of heme. HatRT is comprised of a TetR family transcriptional regulator (hatR) and a major facilitator superfamily transporter (hatT). Strains inactivated for hatR or hatT are more sensitive to heme toxicity than wild-type. HatR binds heme, which relieves the repression of the hatRT operon, whereas HatT functions as a heme efflux pump. In a murine model of CDI, a strain inactivated for hatT displayed lower pathogenicity in a toxin-independent manner. Taken together, these data suggest that HatR senses intracellular heme concentrations leading to increased expression of the hatRT operon and subsequent heme efflux by HatT during infection. These results describe a mechanism employed by C. difficile to relieve heme toxicity within the host, and set the stage for the development of therapeutic interventions to target this bacterial-specific system.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2018-12-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori–induced inflammation–driven gastric carcinogenesis

    Jennifer M. Noto / M. Blanca Piazuelo / Shailja C. Shah / Judith Romero-Gallo / Jessica L. Hart / Chao Di / James D. Carmichael / Alberto G. Delgado / Alese E. Halvorson / Robert A. Greevy / Lydia E. Wroblewski / Ayushi Sharma / Annabelle B. Newton / Margaret M. Allaman / Keith T. Wilson / M. Kay Washington / M. Wade Calcutt / Kevin L. Schey / Bethany P. Cummings /
    Charles R. Flynn / Joseph P. Zackular / Richard M. Peek Jr.

    The Journal of Clinical Investigation, Vol 132, Iss

    2022  Volume 10

    Abstract: Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these ... ...

    Abstract Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori–infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori–infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori–induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein–coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori–induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.
    Keywords Gastroenterology ; Infectious disease ; Medicine ; R
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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