Browsing by Subject "Clostridioides difficile"

Now showing 1 - 5 of 5
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    Fecal Microbiota Transplantation
    (Thieme, 2023-01-25) Cheng, Yao-Wen; Fischer, Monika; Medicine, School of Medicine
    Fecal microbiota transplantation (FMT) is the process of transplanting stool from a healthy donor into the gut of a patient for therapeutic purposes. Current guidelines recommend FMT for the prevention of multiply recurrent Clostridioides difficile infection (CDI) after two recurrences, with cure rates approaching 90%. Emerging evidence also supports the use of FMT in the management of severe and fulminant CDI, resulting in decreased mortality and colectomy rates compared with standard of care approach. FMT shows promise as salvage therapy for critically-ill, refractory CDI patients who are poor surgical candidates. FMT should be considered early in the clinical course of severe CDI, preferably within 48 hours of failing to respond to antibiotic therapy and volume resuscitation. Besides CDI, ulcerative colitis was more recently identified as a potential treatment target for FMT. Several live biotherapeutics for microbiome restoration are on the horizon.
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    Microbiome predictors of dysbiosis and VRE decolonization in patients with recurrent C. difficile infections in a multi-center retrospective study
    (AIMS Press, 2019-01-17) Santiago, Marina; Eysenbach, Lindsay; Allegretti, Jessica; Aroniadis, Olga; Brandt, Lawrence J.; Fischer, Monika; Grinspan, Ari; Kelly, Colleen; Morrow, Casey; Rodriguez, Martin; Osman, Majdi; Kassam, Zain; Smith, Mark B.; Timberlake, Sonia; Medicine, School of Medicine
    The gastrointestinal microbiome is intrinsically linked to the spread of antibiotic resistance. Antibiotic treatment puts patients at risk for colonization by opportunistic pathogens like vancomycin resistant Enterococcus and Clostridioides difficile by destroying the colonization resistance provided by the commensal microbiota. Once colonized, the host is at a much higher risk for infection by that pathogen. Furthermore, we know that microbiome community differences are associated with disease states, but we do not have a good understanding of how we can use these changes to classify different patient populations. To that end, we have performed a multicenter retrospective analysis on patients who received fecal microbiota transplants to treat recurrent Clostridioides difficile infection. We performed 16S rRNA gene sequencing on fecal samples collected as part of this study and used these data to develop a microbiome disruption index. Our microbiome disruption index is a simple index that is predictive across cohorts, indications, and batch effects. We are able to classify pre-fecal transplant vs post-fecal transplant samples in patients with recurrent C. difficile infection, and we are able to predict, using previously-published data from a cohort of patients receiving hematopoietic stem cell transplants, which patients would go on to develop bloodstream infections. Finally, we also identified patients in this cohort that were initially colonized with vancomycin resistant Enterococcus and that 92% (11/12) were decolonized after the transplant, but the microbiome disruption index was unable to predict such decolonization. We, however, were able to compare the relative abundance of different taxa between the two groups, and we found that increased abundance of Enterobacteriaceae predicts whether patients were colonized with vancomycin resistant Enterococcus. This work is an early step towards a better understanding of how microbiome predictors can be used to help improve patient care and patient outcomes.
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    Nonsteroidal anti-inflammatory drugs sensitize epithelial cells to Clostridioides difficile toxin-mediated mitochondrial damage
    (American Association for the Advancement of Science, 2023) Soto Ocaña, Joshua; Bayard, Nile U.; Hart, Jessica L.; Thomas, Audrey K.; Furth, Emma E.; Lacy, D. Borden; Aronoff, David M.; Zackular, Joseph P.; Medicine, School of Medicine
    Clostridioides difficile damages the colonic mucosa through the action of two potent exotoxins. Factors shaping C. difficile pathogenesis are incompletely understood but are likely due to the ecological factors in the gastrointestinal ecosystem, mucosal immune responses, and environmental factors. Little is known about the role of pharmaceutical drugs during C. difficile infection (CDI), but recent studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) worsen CDI. The mechanism underlying this phenomenon remains unclear. Here, we show that NSAIDs exacerbate CDI by disrupting colonic epithelial cells (CECs) and sensitizing cells to C. difficile toxin-mediated damage independent of their canonical role of inhibiting cyclooxygenase (COX) enzymes. Notably, we find that NSAIDs and C. difficile toxins target the mitochondria of CECs and enhance C. difficile toxin-mediated damage. Our results demonstrate that NSAIDs exacerbate CDI by synergizing with C. difficile toxins to damage host cell mitochondria. Together, this work highlights a role for NSAIDs in exacerbating microbial infection in the colon.
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    Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth
    (Public Library of Science, 2023-11-09) He, Aina; Tian, Songhai; Kopper, Oded; Horan, Daniel J.; Chen, Peng; Bronson, Roderick T.; Sheng, Ren; Wu, Hao; Sui, Lufei; Zhou, Kun; Tao, Liang; Wu, Quan; Huang, Yujing; Shen, Zan; Han, Sen; Chen, Xueqing; Chen, Hong; He, Xi; Robling, Alexander G.; Jin, Rongsheng; Clevers, Hans; Xiang, Dongxi; Li, Zhe; Dong, Min; Anatomy, Cell Biology and Physiology, School of Medicine
    Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.
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    Walk before you run: feasibility challenges and lessons learned from the PROCLAIM Study, a multicenter randomized controlled trial of misoprostol for prevention of recurrent C. difficile during COVID-19
    (Elsevier, 2023) Lavieri, Robert R.; Dubberke, Erik R.; McGill, Sarah K.; Bartelt, Luther; Smith, Stephanie A.; Pandur, Balint K.; Phillips, Sharon E.; Vermillion, Krista; Shirey-Rice, Jana; Pulley, Jill; Xu, Yaomin; Lindsell, Christopher J.; Zaleski, Nicole; Jerome, Rebecca; Doster, Ryan S.; Aronoff, David M.; Medicine, School of Medicine
    We analyzed our challenging experience with a randomized controlled trial of misoprostol for prevention of recurrent C. difficile. Despite careful prescreening and thoughtful protocol modifications to facilitate enrollment, we closed the study early after enrolling just 7 participants over 3 years. We share lessons learned, noting the importance of feasibility studies, inclusion of biomarker outcomes, and dissemination of such findings to inform future research design and implementation successes.