Role of interleukin 23 signaling in Clostridium difficile colitis.
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ABSTRACT:
SUBMITTER: Buonomo EL
PROVIDER: S-EPMC3749013 | biostudies-literature | 2013 Sep
REPOSITORIES: biostudies-literature
Publications
Role of interleukin 23 signaling in Clostridium difficile colitis.
Buonomo Erica L EL Madan Rajat R Pramoonjago Patcharin P Li Li L Okusa Mark D MD Petri William A WA
The Journal of infectious diseases 20130617 6
Clostridium difficile is currently the leading cause of hospital-acquired infections in the United States. Here, we observed increased interleukin 23 (IL-23) protein levels in human colon biopsy specimens positive for C. difficile toxins, compared with levels in negative controls (P = .008) We also investigated the role of IL-23 during C. difficile infection, using 2 distinct murine models. Mice lacking IL-23 signaling had a significant increase in survival (100% [12 mice]), compared with contro ...[more]
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Project description:BACKGROUND/AIMS:Clostridium difficile infection (CDI) frequently complicates ulcerative colitis (UC) and can mimic disease flare. Differentiating UC flare from CDI remains a clinical challenge, particularly due to C. difficile colonization. Procalcitonin (PCT) is a serum biomarker for bacterial infections. We hypothesized that PCT would differentiate acute CDI from UC flare and C. difficile colonization. METHODS:A single-center prospective cohort study was conducted from 2013 to 2016. All UC patients with a stool sample for C. difficile testing were eligible. A total of 117 patients were enrolled, while 20 were excluded. Chart review was performed. RESULTS:Among 27 patients with CDI, median PCT was 60.7 (range 26-560.6) pg/mL, while among 90 patients without CDI, median PCT was 56.7 (range 25.1-2,252) pg/mL (p = 0.9). It was found that 14 patients with CDI responded completely to C. difficile treatment (CDI-R), while 8 patients did not and were diagnosed with UC flare (CDI-NR). For CDI-R, median PCT was 104.5 (range 26.3-560.6), compared to 40.3 (range 26.0-116.3) for CDI-NR (p = 0.036). CONCLUSIONS:In UC patients presenting with diarrhea, serum PCT was not significantly higher in UC patients with positive C. difficile testing. However, PCT was significantly elevated in CDI-R versus CDI-NR, suggesting that PCT may have utility in making this discrimination.
| S-EPMC5899687 | biostudies-literature
Project description:UnlabelledClostridium difficile is the most common hospital-acquired pathogen, causing antibiotic-associated diarrhea in over 250,000 patients annually in the United States. Disease is primarily mediated by toxins A and B, which induce potent proinflammatory signaling in host cells and can activate an ASC-containing inflammasome. Recent findings suggest that the intensity of the host response to infection correlates with disease severity. Our lab has identified the proinflammatory cytokine interleukin-23 (IL-23) as a pathogenic mediator during C. difficile infection (CDI). The mechanisms by which C. difficile induces IL-23, however, are not well understood, and the role of toxins A and B in this process is unclear. Here, we show that toxins A and B alone are not sufficient for IL-23 production but synergistically increase the amount of IL-23 produced in response to MyD88-dependent danger signals, including pathogen-associated molecular patterns (PAMPs) and host-derived damage associated molecular patterns (DAMPs). Danger signals also enhanced the secretion of IL-1? in response to toxins A and B, and subsequent IL-1 receptor signaling accounted for the majority of the increase in IL-23 that occurred in the presence of the toxins. Inhibition of inflammasome activation in the presence of extracellular K(+) likewise decreased IL-23 production. Finally, we found that IL-1? was increased in the serum of patients with CDI, suggesting that this systemic response could influence downstream production of pathogenic IL-23. Identification of the synergy of danger signals with toxins A and B via inflammasome signaling represents a novel finding in the mechanistic understanding of C. difficile-induced inflammation.ImportanceClostridium difficile is among the leading causes of death due to health care-associated infection, and factors determining disease severity are not well understood. C. difficile secretes toxins A and B, which cause inflammation and tissue damage, and recent findings suggest that some of this tissue damage may be due to an inappropriate host immune response. We have found that toxins A and B, in combination with both bacterium- and host-derived danger signals, can induce expression of the proinflammatory cytokines IL-1? and IL-23. Our results demonstrate that IL-1? signaling enhances IL-23 production and could lead to increased pathogenic inflammation during CDI.
| S-EPMC4324312 | biostudies-literature
Project description:Clostridium difficile infection (CDI) is the most frequent cause of nosocomial diarrhea. It has become a significant dilemma in the treatment of patients, and causes increasing morbidity that, in extreme cases, may result in death. Persistent and recurrent disease hamper attempts at eradication of this infection. Escalating levels of treatment and novel therapeutics are being utilized and developed to treat CDI. Further trials are warranted to definitively determine what protocols can be used to treat persistent and recurrent disease.
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Project description:BACKGROUND: Many individuals have serum antibodies against Clostridium difficile toxins. Those with an impaired antitoxin response may be susceptible to recurrent, prolonged, or severe C difficile diarrhoea and colitis. AIMS: To examine whether treatment with intravenous immunoglobulin might be effective in patients with severe pseudomembranous colitis unresponsive to standard antimicrobial therapy. PATIENTS: Two patients with pseudomembranous colitis not responding to metronidazole and vancomycin were given normal pooled human immunoglobulin intravenously (200-300 mg/kg). METHODS: Antibodies against C difficile toxins were measured in nine immunoglobulin preparations by ELISA and by cytotoxin neutralisation assay. RESULTS: Both patients responded quickly as shown by resolution of diarrhoea, abdominal tenderness, and distension. All immunoglobulin preparations tested contained IgG against C difficile toxins A and B by ELISA and neutralised the cytotoxic activity of C difficile toxins in vitro at IgG concentrations of 0.4-1.6 mg/ml. CONCLUSION: Passive immunotherapy with intravenous immunoglobulin may be a useful addition to antibiotic therapy for severe, refractory C difficile colitis. IgG antitoxin is present in standard immunoglobulin preparations and C difficile toxin neutralising activity is evident at IgG concentrations which are readily achieved in the serum by intravenous immunoglobulin administration.
| S-EPMC1891485 | biostudies-other
Project description:Clostridium difficile is being recognized as a growing threat to many health-care systems. Epidemiology data shows that infection rates are soaring and the disease burden is increasing. Despite the efficacy of standard treatments, it is becoming evident that novel therapeutics will be required to tackle this disease. These new treatments aim to enhance the intestinal microbial barrier, activate the immune system and neutralize the toxins that mediate this disease. Many of these therapies are still in the beginning stages of investigation, however, in the next few years, more clinical data will become available to help implement many of these exciting new therapeutic approaches.
| S-EPMC5979265 | biostudies-literature
Project description:Patients with inflammatory bowel disease (IBD) are at higher risk for Clostridium difficile infection (CDI). Disruption of gut microbiome and interaction with the intestinal immune system are essential mechanisms for pathogenesis of both CDI and IBD. Whether genetic polymorphisms associated with susceptibility to IBD are also associated with risk of CDI is unknown.To use a well-characterised and genotyped cohort of patients with UC to (i) identify clinical risk factors for CDI; (ii) examine if any of the IBD genetic risk loci were associated with CDI; and (iii) to compare the performance of predictive models using clinical and genetic risk factors in determining risk of CDI.We used a prospective registry of patients from a tertiary referral hospital. Medical record review was performed to identify all ulcerative colitis (UC) patients within the registry with a history of CDI. All patients were genotyped on the Immunochip. We examined the association between the 163 risk loci for IBD and risk of CDI using a dominant genetic model. Model performance was examined using receiver operating characteristics curves.The study included 319 patients of whom 29 developed CDI (9%). Female gender and pancolitis were associated with increased risk, while use of anti-TNF was protective against CDI. Six genetic polymorphisms including those at TNFRSF14 [Odds ratio (OR) 6.0, P-value 0.01] were associated with increased risk while 2 loci were inversely associated. On multivariate analysis, none of the clinical parameters retained significance after adjusting for genetics. Presence of at least one high-risk locus was associated with an increase in risk for CDI (20% vs. 1%) (P = 6 × 10??). Compared to 11% for a clinical model, the genetic loci explained 28% of the variance in CDI risk and had a greater AUROC.Host genetics may influence susceptibility to Clostridium difficile infection in patients with ulcerative colitis.
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Project description:To review the most recent data regarding the epidemiology, risks factors, and outcomes among hematopoietic stem cell transplant recipients with Clostridium difficile infection (CDI).With the emergence of an epidemic strain of C. difficile known as NAP1 in the early 2000s, rates of this infection have escalated globally. Hematopoietic stem cell transplant recipients appear to be one of the most vulnerable populations for the development of CDI. Traditional risk factors for CDI including antimicrobial exposure and older age are likely only a piece of the overall risk profile, with recent study results also emphasizing other factors such as transplant type, conditioning regimen, and graft-versus-host disease (GVHD). The relationship between CDI and subsequent development of GVHD, particularly of the gastrointestinal tract, is of specific interest. A bidirectional relationship of association has been highlighted in a number of recent studies and underscores the need for further prospective studies to address the potential indirect effects of alloreactivity induced by CDI.CDI has emerged as one of the most common infections in the early transplant period. Recent studies have begun to address the epidemiology of disease, risk factors for, and outcomes after infection in the stem cell transplant. However, more research is needed to unravel the observed relationship between CDI and GVHD.
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Project description:BackgroundUlcerative colitis (UC) is an inflammatory bowel disease (IBD) that is widely identified worldwide. This study aimed to investigate the phenotypic characterization and molecular typing of Clostridium difficile isolates among patients with UC at an inflammatory bowel disease clinic in Iran.MethodsIn this cross-sectional study, conducted from April 2015 to December 2015, 85 UC patients were assessed for C.difficile infection (CDI). C. difficile isolates were characterized based on their toxin profile and antimicrobial resistance pattern. Multi-locus sequence typing analysis (MLST) and PCR ribotyping were performed to define the genetic relationships between different lineages of toxigenic strains.ResultsThe prevalence of C. difficile isolates was 31.8% (27/85) in patients, of those 15 patients (17.6%) had CDI. Three different sequence types (STs) identified based on MLST among the toxigenic isolates, that is ST54 (33.3%), ST2 (53.3%), and ST37 (13.6%). C. difficile strains were divided into four different PCR-ribotypes (012, 014, 017 and IR1). The most common ribotype was 014 accounting for 48.3% (7/15) of all strains. The strains isolated during the first episode and recurrence of CDI usually belonged to PCR ribotype 014 (ST2). A high rate of CDI recurrence (14.1%, 12/85) experienced in UC patients. Colonization of the gastrointestinal tract with non-toxigenic C. difficile strains was frequent among patients with mild disease. All C. difficile isolates were susceptible to metronidazole, and vancomycin, 86 and 67% of isolates were resistant to clindamycin and erythromycin respectively. There was no correlation between the toxin type and antibiotic resistance (p > 0.05).ConclusionOverall CDI is rather prevalent in UC patients. All patients with CDI experienced moderate to severe disease and exposed to different antimicrobial and anti-inflammatory agents. Close monitoring and appropriate management including early detection and fast treatment of CDI will improve UC outcomes.
| S-EPMC6492486 | biostudies-literature