C Diff Molecular

To better understand how microbes affect our health, researchers combined 119 species of bacteria naturally found in the human body.

Intestinal microbiome disruption is associated with recurrent Clostridioides difficile infection (rCDI), which poses a high risk of morbidity and mortality. Microbiome-based therapeutics are increasingly evaluated as a strategy to reduce rCDI, and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid (BA) metabolism. This study reports the development of a highly quantitative and sensitive assay for targeted metabolomic assessment of bile acids, and the application of the assay to profile bile acid composition in a Phase 2 trial of the investigational microbiota-based live biotherapeutic RBX2660 for reduction of rCDI (PUNCH CD2; [NCT02299570][1]). Participants were asked to provide stool samples before and up to 24 months after treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 35 BAs from a total of 113 participant stool samples from 27 rCDI participants treated with RBX2660 in the double-blinded, placebo-controlled clinical trial. The results demonstrate a high-confidence assay as represented by sensitivity, linearity, accuracy, and precision of the output measurements of BAs. When the assay was utilized to assess stool samples from the clinical trial participants, primary BAs were the dominant BA species at baseline, consistent with the expected loss of commensals after broad-spectrum antibiotic treatment. As early as 7 days after RBX2660 administration, there was a significant drop in primary BAs concurrent with increased secondary BAs, and this profile was sustained through 24 months after RBX2660 administration. Taken together, we describe a robust assay that demonstrates altered BA metabolism associated with RBX2660 administration, shifting towards a profile that is consistent with a healthier BA profile and clinical response. ### Competing Interest Statement RP, NF, KS, and BCF are employees of Ferring Pharmaceuticals. KB is an employee of Rebiotix Inc., a Ferring company. CG and BS are employed by BioRankings, LLC, which received fees for this analysis from Rebiotix Inc., a Ferring company. ### Clinical Trial NCT02299570 ### Funding Statement The work was supported by Rebiotix Inc., a Ferring company, and the Ferring Research Institute of Ferring Pharmaceuticals. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional review board/research ethics board (IRB/REB) at each participating center approved the study protocol and informed consent form (Quorum Review, University of Chicago Biological Sciences Division/University of Chicago Medical Center; Western IRB; Louis Stokes Cleveland Department of Veterans Affairs Medical Center IRB; Henry Ford Health System IRB; University of Pennsylvania Institutional Review Board; St. Vincents Hospital and Health Care Center, Inc IRB; Loyola University Chicago Health Sciences Division Institutional Review Board for the Protection of Human Subjects; Mayo Clinic Institutional Review Boards; Weill Cornell Medical College IRB; IRB of St. Ritas Health Partners; HealthPartners Institute for Education and Research IRB; Hamilton Integrated Research Ethics Board; University of British Columbia Clinical Research Ethics Board; Washington University Human Research Protection Office). All study participants provided written informed consent. An independent medical monitor provided safety oversight. All methods were carried out in accordance with relevant guidelines and regulations. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets presented in this article are not readily available because they are restricted by an ongoing commercialization process. Requests to access the datasets should be directed to KB. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02299570&atom=%2Fmedrxiv%2Fearly%2F2022%2F09%2F01%2F2022.08.30.22278604.atom

.@gianluca1aniro: C. difficile infection is a simple model of dysbiosis. The decrease of secondary bile salts due to antibiotic treatment is a major contributor that favours vegetative growth of C. difficile @esnm_eu #GMFHCoverage pic.twitter.com/G6IMSIlVj6— GutMicrobiota Health (@GMFHx) September 6, 2022

Nature Communications - Here the authors present a large-scale resource of the early-life human gut microbiome from children under three years old, which comprises 32,277 metagenome-assembled gut...

The second messenger c-di-AMP contributes to various homeostatic and stress responses in bacteria. In this issue of Science Signaling, Oberkampf et al. have identified it as a mediator of osmotic stress and bile salt resistance in the opportunistic pathogen Clostridioides difficile …

A Clostridioides difficile strain deficient in the ddl gene is unable to synthesize the dipeptide D-Ala-D-Ala, an essential component of peptidoglycan and the target of vancomycin. We isolated spontaneous suppressors of a ∆ddl mutation that allowed cell growth in the absence of D-Ala-D-Ala. The muta …

Clostridioides difficile is a spore-forming anaerobic Gram-positive bacterium responsible for a broad spectrum of intestinal symptoms and healthcare associated diarrhoea. The hypothesis of this work was that different in vitro conditions, notably pH and human faecal microbiota composition impact the …

Communications Biology - Clostridium novyi alpha-toxin (Tcnα) also uses LRP1 and Megalin as cellular entry receptors besides LDLR, and this might be a response to cell-type dependent receptor...

Clostridioides difficile is a spore-forming anaerobic Gram-positive bacterium responsible for a broad spectrum of intestinal symptoms and healthcare associated diarrhoea. The hypothesis of this work was that different in vitro conditions, notably pH and human faecal microbiota composition impact the …

Clostridioides difficile is a Gram-positive bacillus, which is a frequent cause of gastrointestinal infections triggered by the depletion of the gut microbiome. Because of the frequent recurrence of these infections after antibiotic treatment, mechanisms of C. difficile persistence and recurrence, i …

Nature Microbiology - Characterization of a biosynthetic pathway for the sulfonation of steroidal metabolites, such as cholesterol, by gut bacteria may have implications for immune cell trafficking...

A gastroenterologist, Dr. Bincy Abraham, provides an overview of C. difficile infection (CDI) in patients with inflammatory bowel disease (IBD).

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated intestinal disease, resulting in severe diarrhea and fatal pseudomembranous colitis. TcdB, one of the essential virulence factors secreted by this bacterium, induces host cell apoptosis through a poorly understood …

When compared to those without IBD, patients with IBD have a reduced proportion of cases of C. difficile with toxin positivity. Differences in clinical outcomes among patients with IBD were not detected and limited by the infrequent detection of expressed toxin.

Although this study does not support the claim that Clostridium difficile and/or H. pylori have a role in UC, it greatly suggests that pathogenic E. coli may be involved in one way or another in the course of UC.

Toxins TcdA and TcdB from Clostridioides difficile glucosylate human colon Rho GTPases. TcdA and TcdB glucosylation of RhoGTPases results in cytoskeletal changes, causing cell rounding and loss of intestinal integrity. Clostridial toxins TcdA and TcdB are proposed to catalyze glucosylation of …

Clostridium difficile (C. difficile) is a multi-strain, spore-forming, Gram-positive, opportunistic enteropathogen bacteria, majorly associated with nosocomial infections, resulting in severe diarrhoea and colon inflammation. Several antibiotics including penicillin, tetracycline, and …

Clostridioides difficile (C. difficile) is a Gram-positive, spore-forming, toxin-producing, obligate anaerobic bacterium. C. difficile infection (CDI) is the leading cause of health-care-associated infective diarrhea. The infection is mediated by the spore, a metabolically inact …

The patient-derived Clostridioides difficile bacterial strain was found to drive colon tumorigenesis through its toxin TcdB, which induced Wnt signaling and a protumorigenic mucosal immune response.

Clostridioides difficile is an important health care-associated pathogen. The aim of this study was to analyze the antibiotic susceptibility of C. difficile isolates from feces of patients from 13 hospitals in Silesia, Poland. The incidence of CDI per 100.000 people in Silesia in 2018- …

Clostridioides (Clostridium) difficile infection (CDI) is an evolving global healthcare problem, and owing to the diverse and dynamic molecular epidemiology of C. difficile, new strains continue to emerge. In Brazil, only two cases of CDI due to the so called hypervirulent PCR ribotype (RT) 027 belo …

Biochemical Characterizations of the Putative Endolysin Ecd09610 Catalytic Domain from Clostridioides difficile https://t.co/oZPXRD6mGo #cdi #cdiff— Dave Roberts (@CDifficile1) August 28, 2022

Clostridioides difficile is the major pathogen of pseudomembranous colitis, and novel antimicrobial agents are sought after for its treatment. Phage-derived endolysins with species-specific lytic activity have potential as novel antimicrobial agents. We surveyed the genome of C. difficile …

Not sure who needs to hear this, but:#metronidazole can be q12h and not q8h for everything except CNS infections & fulminant #cdiff#idtwitter #MedTwitter #idcrit @IdVilchez @IDstewardship— James Wilson, DO, FAWM (@JamesWilsonDO1) August 25, 2022

Clostridioides (Clostridium) difficile infection (CDI) is an evolving global healthcare problem, and owing to the diverse and dynamic molecular epidemiology of C. difficile, new strains continue to emerge. In Brazil, only two cases of CDI due to the so called hypervirulent PCR ribotype (RT) 027 belo …

Clostridioides difficile is an important health care-associated pathogen. The aim of this study was to analyze the antibiotic susceptibility of C. difficile isolates from feces of patients from 13 hospitals in Silesia, Poland. The incidence of CDI per 100.000 people in Silesia in 2018- …

C. difficile enterocolitis (CDAC) is the most common hospital infection, burdened by an increased incidence of coagulation-related complications such as deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC) as well as a significant sepsis-related mortality. In this revie …

The role of fungal colonizers of the gastrointestinal tract during disease states is not well understood. Antibiotic treatment renders patients highly susceptible to infection by the bacterial pathogen C. difficile while also leading to blooms in fungal commensals, setting the stage for trans-kingdo …