The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection

Sun, Xingmin; Hirota, Simon A.

doi:10.1016/j.molimm.2014.09.005

Cited by 73 publications

(51 citation statements)

References 160 publications

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“…4,6 Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD), Ulcerative Colitis (UC), and patients after ileal pouch anal anastomosis (IPAA), is known to be an independent risk factor for CDI. 4,9,10 In this population, traditional risk factors do not have the same correlation with symptomatic infection. Proton-pump inhibitors are a less common risk 11 and in children colonization is more common over symptomatic disease.…”

Section: Introductionmentioning

confidence: 75%

“…27 Normal gut flora is needed to compete with C. difficile for nutrients and regulate transformation of bile salts, particularly taucholate, which is needed for C. difficile germination. 10,25 In its vegetative state C. difficile produces toxins which enter the cell and damage the intestinal epithelial cytoskeleton, 17,26 act as a chemoattractant for neutrophils and lead to inflammation. It is this inflammatory response, not the degree of bacterial burden, which leads to cell injury and determines the clinical severity of CDI.…”

Section: Discussionmentioning

confidence: 99%

“…Previous data show that up to 60% of older children and adults in the general population have antibodies to C. difficile toxin A and B. 10 Early studies showed toxin antibody levels do not offer initial protection against colonization 23 but are correlated with the occurrence of symptomatic disease. Kyne et al 24 found that higher levels of Toxin A IgM on day 3 and IgG on day 12 after onset of c. difficile diarrhea were associated with single-episode CDI without recurrence.…”

Section: Discussionmentioning

confidence: 99%

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Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

Hughes

Qazi

Berg

et al. 2016

Inflammatory Bowel Diseases

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Background Clostridium difficile infection affects IBD patients. This study’s aim was to compare humoral response to C. difficile toxins in IBD and control outpatients. Methods We prospectively followed adult IBD and control subjects with serum and stool tested by PCR obtained at enrollment and during periods of CDI. Semi-quantitative serum levels of IgM, IgG and IgA to C. difficile toxins A and B were measured. Results 119 stool and 117 serum samples were obtained from 150 subjects. Different levels of IgA to toxin A (p=0.0016) and toxin B (p=0.0468) were noted between different IBD groups. Toxin A IgA levels were higher in the CD group (p=0.0321) and IPAA group (p=0.001) compared to the UC group and toxin B IgA levels were higher in the IPAA group compared to the UC group (p=0.0309). There were lower levels of toxin A IgA in IBD patients with compared with those in subjects without new CDI (P=0.0488) and higher levels in IBD patients with compared with those in subjects without CDI history before enrollment (P=0.016). There were nonsignificant lower toxin A IgG levels in IBD patients with compared to without prior CDI (p=0.095) and higher levels in controls with history of prior CDI compared to IBD patients with prior CDI (p=0.049). Conclusions UC patients have lower IgA levels to C. difficile toxins compared to Crohn’s and IPAA patients. IBD patients with prior CDI failed to demonstrate any increase in anti-toxin IgG. Our findings suggest that IBD patients may benefit from immunization strategies targeting C. difficile toxins.

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Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

Hughes

Qazi

Berg

et al. 2016

Inflammatory Bowel Diseases

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“…Although the mechanism of its hypervirulence is not fully elucidated, this strain is fluoroquinolone resistant (12) and appears to produce more toxin A and toxin B than any other C. difficile strains (35). The binary toxin also possesses cytotoxic activity, but its role in CDI is still not well understood (48). Based on these considerations, the in vivo and in vitro effects of S.b in C. difficile ribotype 027 may be directed against toxin A, toxin B, and/or the binary toxin.…”

Section: Discussionmentioning

confidence: 99%

ProbioticSaccharomyces boulardiiCNCM I-745 prevents outbreak-associatedClostridium difficile-associated cecal inflammation in hamsters

Koon

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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. difficile infection (CDI) is a common debilitating nosocomial infection associated with high mortality. Several CDI outbreaks have been attributed to ribotypes 027, 017, and 078. Clinical and experimental evidence indicates that the nonpathogenic yeast Saccharomyces boulardii CNCM I-745 (S.b) is effective for the prevention of CDI. However, there is no current evidence suggesting this probiotic can protect from CDI caused by outbreak-associated strains. We used established hamster models infected with outbreak-associated C. difficile strains to determine whether oral administration of live or heat-inactivated S.b can prevent cecal tissue damage and inflammation. Hamsters infected with C. difficile strain VPI10463 (ribotype 087) and outbreakassociated strains ribotype 017, 027, and 078 developed severe cecal inflammation with mucosal damage, neutrophil infiltration, edema, increased NF-B phosphorylation, and increased proinflammatory cytokine TNF␣ protein expression. Oral gavage of live, but not heated, S.b starting 5 days before C. difficile infection significantly reduced cecal tissue damage, NF-B phosphorylation, and TNF␣ protein expression caused by infection with all strains. Moreover, S.b-conditioned medium reduced cell rounding caused by filtered supernatants from all C. difficile strains. S.b-conditioned medium also inhibited toxin A-and B-mediated actin cytoskeleton disruption. S.b is effective in preventing C. difficile infection by outbreak-associated via inhibition of the cytotoxic effects of C. difficile toxins. (46). C. difficile is an anaerobic bacterium that produces two toxins -toxin A and toxin B -that mediate diarrhea, inflammation, and apoptosis of the mucosal epithelium in animals and humans (32). The effects of the toxin in target intestinal cells involve inactivation of the Rho family of GTPase, leading to cytoskeletal disorganization, epithelial cell apoptosis, and ultimately cell death (42, 54). C. difficile toxins also stimulate transcription of several proinflammatory genes, including tumor necrosis factor-␣ (TNF␣) (19) and activate transcription factors and mitogen-activated protein kinases involved in their proinflammatory effects (18,25). The mainstream CDI regimen includes the use of metronidazole, vancomycin, and fidaxomicin (55). However, many C. difficileinfected patients may also suffer from recurrent infections (13), while the recent epidemics that also involve new epidemic outbreak-associated strains (29) pose a major medical problem and epidemiological concern. These challenges have been met with a broad range of preventive approaches against CDI, including the use of probiotics, most notably Saccharomyces boulardii (S.b) alone or in combination with established antibiotic treatment (23,24).S.b is a nonpathogenic yeast that represents one of the well-studied probiotics against CDI in both experimental and clinical settings (24,40). Randomized double-blind placebocontrolled clinical trials have shown that S.b CNCM I-745 is an effective probiotic in the prophylaxis of antibi...

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“…C. difficile -associated diarrhoea and colitis occurs secondary to elaborated toxins that activate epithelial inflammatory signalling pathways and recruit immune cells. 68 …”

Section: Mechanisms Of Diarrhoeal Diseasementioning

confidence: 99%

Secretory diarrhoea: mechanisms and emerging therapies

Thiagarajah

Donowitz

Verkman

2015

Nat Rev Gastroenterol Hepatol

179

137

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Diarrhoeal disease remains a major health burden worldwide. Secretory diarrhoeas are caused by certain bacterial and viral infections, inflammatory processes, drugs and genetic disorders. Fluid secretion across the intestinal epithelium in secretory diarrhoeas involves multiple ion and solute transporters, as well as activation of cyclic nucleotide and Ca2+ signalling pathways. In many secretory diarrhoeas, activation of Cl− channels in the apical membrane of enterocytes, including the cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels, increases fluid secretion, while inhibition of Na+ transport reduces fluid absorption. Current treatment of diarrhoea includes replacement of fluid and electrolyte losses using oral rehydration solutions, and drugs targeting intestinal motility or fluid secretion. Therapeutics in the development pipeline target intestinal ion channels and transporters, regulatory proteins and cell surface receptors. This Review describes pathogenic mechanisms of secretory diarrhoea, current and emerging therapeutics, and the challenges in developing antidiarrhoeal therapeutics.

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The roles of host and pathogen factors and the innate immune response in the pathogenesis of Clostridium difficile infection

Cited by 73 publications

References 160 publications

Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

Host Immune Response to Clostridium difficile Infection in Inflammatory Bowel Disease Patients

ProbioticSaccharomyces boulardiiCNCM I-745 prevents outbreak-associatedClostridium difficile-associated cecal inflammation in hamsters

Secretory diarrhoea: mechanisms and emerging therapies

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