C. difficile infection gut microbiome
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB57947 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10674300_1.fastq.gz | Fastqsanger.gz | |||
| ERR10674300_2.fastq.gz | Fastqsanger.gz | |||
| ERR10674400_1.fastq.gz | Fastqsanger.gz | |||
| ERR10674400_2.fastq.gz | Fastqsanger.gz | |||
| ERR10674500_1.fastq.gz | Fastqsanger.gz |
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Project description:The pathogen Clostridioides difficile causes toxin-mediated diarrhea and is the leading cause of hospital-acquired infection in the United States. Due to growing antibiotic resistance and recurrent infection, targeting C. difficile metabolism presents a new approach to combat this infection. Genome-scale metabolic network reconstructions (GENREs) have been used to identify therapeutic targets and uncover properties that determine cellular behaviors. Thus, we constructed C. difficile GENREs for a hypervirulent isolate (strain [str.] R20291) and a historic strain (str. 630), validating both with in vitro and in vivo data sets. Growth simulations revealed significant correlations with measured carbon source usage (positive predictive value [PPV] ≥ 92.7%), and single-gene deletion analysis showed >89.0% accuracy. Next, we utilized each GENRE to identify metabolic drivers of both sporulation and biofilm formation. Through contextualization of each model using transcriptomes generated from in vitro and infection conditions, we discovered reliance on the pentose phosphate pathway as well as increased usage of cytidine and N-acetylneuraminate when virulence expression is reduced, which was subsequently supported experimentally. Our results highlight the ability of GENREs to identify novel metabolite signals in higher-order phenotypes like bacterial pathogenesis.
2023-11-27 | MODEL2205060002 | BioModels
Project description:We illustrate how metabolically distinct species of Clostridia can protect against or worsen Clostridioides difficile infection, modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survived infection while mice colonized with the butyrate-producer, Clostridium sardiniense, more rapidly succumbed. Systematic in vivo analyses revealed how each commensal altered the gut nutrient environment, modulating the pathogen's metabolism, regulatory networks, and toxin production. Oral administration of P. bifermentans rescued conventional mice from lethal C. difficile infection via mechanisms identified in specifically colonized mice. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biologic approaches to define host-commensal-pathogen interactions in vivo.
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Project description:Unraveling Cecal Alterations in Clostridioides difficile Colonized Mice through a Comprehensive Metabolic Profile of 289 Compound
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Project description:The intestines house a diverse microbiota that must compete for nutrients to survive, but the specific limiting nutrients that control pathogen colonization are not clearly defined. Clostridioides difficile colonization typically requires prior disruption of the microbiota, suggesting that outcompeting commensals for resources is key in establishing C. difficile infection (CDI). The immune protein calprotectin (CP) is released into the gut lumen during CDI to chelate zinc (Zn) and other essential nutrient metals. Yet, the impact of Zn limitation on C. difficile colonization is unknown. To define C. difficile responses to Zn limitation, we performed RNA sequencing on C. difficile exposed to CP. In media with CP, C. difficile upregulated genes involved in metal homeostasis and amino acid metabolism.
2019-10-24 | GSE135912 | GEO
Project description:Clostridioides difficile is a major cause of healthcare-associated diarrhea in adult patients. Laboratory diagnosis of C. difficile infection (CDI) is challenging as there is no single test combining high sensitivity and specificity, rapid turnaround time and cost efficiency. They also offer no or little correlation with the clinical outcome. Recently, host-based methods have shown satisfactory performance for the diagnosis of infectious diseases. The aim of this study was to discover CDI-specific host biomarkers that correlate with disease stage and severity.
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Project description:Leber2015 - Mucosal immunity and gut
microbiome interaction during C. difficile infection
This model is described in the article:
Systems Modeling of
Interactions between Mucosal Immunity and the Gut Microbiome
during Clostridium difficile Infection.
Leber A, Viladomiu M, Hontecillas R,
Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera
J.
PLoS ONE 2015; 10(7): e0134849
Abstract:
Clostridium difficile infections are associated with the use
of broad-spectrum antibiotics and result in an exuberant
inflammatory response, leading to nosocomial diarrhea, colitis
and even death. To better understand the dynamics of mucosal
immunity during C. difficile infection from initiation through
expansion to resolution, we built a computational model of the
mucosal immune response to the bacterium. The model was
calibrated using data from a mouse model of C. difficile
infection. The model demonstrates a crucial role of T helper 17
(Th17) effector responses in the colonic lamina propria and
luminal commensal bacteria populations in the clearance of C.
difficile and colonic pathology, whereas regulatory T (Treg)
cells responses are associated with the recovery phase. In
addition, the production of anti-microbial peptides by inflamed
epithelial cells and activated neutrophils in response to C.
difficile infection inhibit the re-growth of beneficial
commensal bacterial species. Computational simulations suggest
that the removal of neutrophil and epithelial cell derived
anti-microbial inhibitions, separately and together, on
commensal bacterial regrowth promote recovery and minimize
colonic inflammatory pathology. Simulation results predict a
decrease in colonic inflammatory markers, such as neutrophilic
influx and Th17 cells in the colonic lamina propria, and length
of infection with accelerated commensal bacteria re-growth
through altered anti-microbial inhibition. Computational
modeling provides novel insights on the therapeutic value of
repopulating the colonic microbiome and inducing regulatory
mucosal immune responses during C. difficile infection. Thus,
modeling mucosal immunity-gut microbiota interactions has the
potential to guide the development of targeted fecal
transplantation therapies in the context of precision medicine
interventions.
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2024-09-02 | BIOMD0000000583 | BioModels
Project description:We defined global differences in transcriptome profiles between mice inoculated with toxin mutant strains of Clostridioides difficile. These data were mined to study differences in expression of ion transporters that may be implicated in diarrhea during disease.
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Project description:The Clostridioides difficile toxins TcdA and TcdB are responsible for diarrhea and colitis. The aim of this project was to explore the effects of the toxins on epithelial barrier function and the molecular mechanisms for diarrhea and inflammation. RNA-seq of toxin-treated intestinal cell monolayers was performed to describe the C. difficile-mediated effects. mRNA profiles from intestinale epithelial cells were generated by deep sequencing using Illumina NovaSeq 6000. This data provide the basis for subsequent upstream regulator analysis.
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Project description:Clostridioides difficile interactions with the gut mucosa are crucial for colonisation and establishment of infection, however key infection events during the establishment of disease are still poorly defined. To better understand the initial events that occur during C. difficile colonisation, we employed a dual RNA-sequencing approach to study the host and bacterial transcriptomic profiles during C. difficile infection in a dual-environment in vitro human gut model. Temporal changes in gene expression were analysed over 3-24h post infection and comparisons were made with uninfected controls.
2023-03-23 | E-MTAB-12660 | biostudies-arrayexpress
Project description:Recurrent Clostridioides difficile infection (CDI) results in significant morbidity and mortality. We previously established that CDI in mice did not protect against reinfection and was associated with poor pathogen-specific B cell memory (Bmem), recapitulating our observations with human Bmem. Herein, we demonstrate that the secreted toxin TcdB2 is responsible for subversion of Bmem responses. TcdB2 from an endemic C. difficile strain delayed IgG class switch following vaccination, attenuated IgG recall to a vaccine booster, and prevented germinal center formation. The mechanism of TcdB2 action included increased B cell CXCR4 expression and responsiveness to its ligand CXCL12, accounting for altered cell migration and a failure of germinal center-dependent Bmem. These results were reproduced in a C. difficile infection model and an FDA-approved CXCR4-blocking drug rescued germinal center formation. We therefore provide mechanistic insights into C. difficile-associated pathogenesis and illuminate a target for clinical intervention to limit recurrent disease.
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