The Enterotoxicity of Clostridium difficile Toxins

Sun, Xingmin; Savidge, Tor; Feng, Hanping

doi:10.3390/toxins2071848

Cited by 93 publications

(152 citation statements)

References 209 publications

(262 reference statements)

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“…Previously, the role of many chemokines and proinflammatory mediators in TcdA-induced enteritis has been studied individually with ileal loops or in vitro (27). For example, Morteau et al found increased Ccl3 and Ccl5 transcription in whole tissue 1 h after TcdA injection and showed that Ccl3 knockout mice were less susceptible to TcdA (30).…”

Section: Discussionmentioning

confidence: 99%

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In VivoPhysiological and Transcriptional Profiling Reveals Host Responses to Clostridium difficile Toxin A and Toxin B

et al. 2013

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Toxin A (TcdA) and toxin B (TcdB) of Clostridium difficile cause gross pathological changes (e.g., inflammation, secretion, and diarrhea) in the infected host, yet the molecular and cellular pathways leading to observed host responses are poorly understood. To address this gap, we evaluated the effects of single doses of TcdA and/or TcdB injected into the ceca of mice, and several endpoints were analyzed, including tissue pathology, neutrophil infiltration, epithelial-layer gene expression, chemokine levels, and blood cell counts, 2, 6, and 16 h after injection. In addition to confirming TcdA's gross pathological effects, we found that both TcdA and TcdB resulted in neutrophil infiltration. Bioinformatics analyses identified altered expression of genes associated with the metabolism of lipids, fatty acids, and detoxification; small GTPase activity; and immune function and inflammation. Further analysis revealed transient expression of several chemokines (e.g., Cxcl1 and Cxcl2). Antibody neutralization of CXCL1 and CXCL2 did not affect TcdA-induced local pathology or neutrophil infiltration, but it did decrease the peripheral blood neutrophil count. Additionally, low serum levels of CXCL1 and CXCL2 corresponded with greater survival. Although TcdA induced more pronounced transcriptional changes than TcdB and the upregulated chemokine expression was unique to TcdA, the overall transcriptional responses to TcdA and TcdB were strongly correlated, supporting differences primarily in timing and potency rather than differences in the type of intracellular host response. In addition, the transcriptional data revealed novel toxin effects (e.g., altered expression of GTPase-associated and metabolic genes) underlying observed physiological responses to C. difficile toxins.

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Section: Discussionmentioning

confidence: 99%

“…It has been difficult to tease apart the aspects of the host response to TcdA and TcdB because of the important interactions among the many tissues, cell types, and signals involved (27,28). The intestinal epithelium, the initial barrier to these toxins, continuously interacts with surrounding cells throughout the development and resolution of disease.…”

mentioning

confidence: 99%

In VivoPhysiological and Transcriptional Profiling Reveals Host Responses to Clostridium difficile Toxin A and Toxin B

et al. 2013

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“…Together, these inflammation-related activities contribute to the progressive ablation of gastrointestinal function that is characteristic of CDI. In animal models, the administration of purified C. difficile TcdA induces the hallmark symptoms of an acute, pseudomembranous colitislike condition: edema, gastrointestinal inflammation, cellular necrosis, and gastroenteritis in the absence of the bacterium (19,(21)(22)(23). The administration of TcdB elicits similar effects, albeit to a lesser degree (22,24).…”

mentioning

confidence: 80%

Effective Sequestration of Clostridium difficile Protein Toxins by Calcium Aluminosilicate

Sturino

Pokusaeva

Carpenter³

2015

Antimicrob Agents Chemother

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c Clostridium difficile is a leading cause of antibiotic-associated diarrhea and the etiologic agent responsible for C. difficile infection. Toxin A (TcdA) and toxin B (TcdB) are nearly indispensable virulence factors for Clostridium difficile pathogenesis. Given the toxin-centric mechanism by which C. difficile pathogenesis occurs, the selective sequestration with neutralization of TcdA and TcdB by nonantibiotic agents represents a novel mode of action to prevent or treat C. difficile-associated disease. In this preclinical study, we used quantitative enzyme immunoassays to determine the extent by which a novel drug, calcium aluminosilicate uniform particle size nonswelling M-1 (CAS UPSN M-1), is capable of sequestering TcdA and TcdB in vitro. The following major findings were derived from the present study. First, we show that CAS UPSN M-1 efficiently sequestered both TcdA and TcdB to undetectable levels. Second, we show that CAS UPSN M-1's affinity for TcdA is greater than its affinity for TcdB. Last, we show that CAS UPSN M-1 exhibited limited binding affinity for nontarget proteins. Taken together, these results suggest that ingestion of calcium aluminosilicate might protect gastrointestinal tissues from antibiotic-or chemotherapy-induced C. difficile infection by neutralizing the cytotoxic and proinflammatory effects of luminal TcdA and TcdB.C lostridium difficile is a leading cause of antibiotic-associated diarrhea (AAD) and is the etiologic agent responsible for C. difficile-associated infection (CDI). CDI typically starts as a mild diarrhea but rapidly degenerates into a variety of potentially lifethreatening conditions, including sepsis syndrome and pseudomembranous colitis (1). In the United States, approximately 330,000 cases of CDI are estimated to occur each year (2); however, the incidence of C. difficile infection continues to increase (2, 3). The increasing CDI rates highlight the fact that the current infection control procedures and treatment options are insufficient.In the health care setting, C. difficile endospores are transmitted to patients via the fecal-oral route (4). Following exposure, the host's gastrointestinal microbiota typically either quells a nascent C. difficile infection or suppresses it to subclinical levels (5). As a result of the latter, approximately 20% of hospitalized adults become asymptomatic C. difficile carriers, and the carriage rates approach 50% for patients in long-term care (6-9). The likelihood of development of CDI increases in patients with dysbiotic gastrointestinal microbiota, since C. difficile can thrive in the dysbiotic niche (5, 10). This dysbiosis is often the result of nonspecific chemotherapies that are used to treat conditions unrelated to C. difficile infection (e.g., antibacterial agents or antineoplastic drugs).The antibiotics metronidazole and vancomycin are currently used to treat CDI (11). Unfortunately, given the conflicting roles of antibiotics in the establishment and resolution of CDI, C. difficile AAD recurs in up to 1 in 5 patients (12)...

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“…The main virulence factors of C. difficile are represented by two exotoxins, toxin A (TcdA) and toxin B (TcdB), similar in structure and mechanisms of action [47] (although TcdB is about 1000-fold more potent than TcdA [48]). Both toxins are able to cause adverse effects in enteric cell populations, such as enterocytes, colonocytes, and enteric neurons [47,49].…”

Section: Pi-ibs After C Difficile Infection: a Case Of A Microbiologmentioning

confidence: 99%

“…Both toxins are able to cause adverse effects in enteric cell populations, such as enterocytes, colonocytes, and enteric neurons [47,49].…”

Section: Pi-ibs After C Difficile Infection: a Case Of A Microbiologmentioning

confidence: 99%

Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum?

Bassotti

Macchioni

Corazzi

et al. 2017

Cell. Mol. Life Sci.

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Post-infectious irritable bowel syndrome is a well-defined pathological entity that develops in about one-third of subjects after an acute infection (bacterial, viral) or parasitic infestation. Only recently it has been documented that an high incidence of post-infectious irritable bowel syndrome occurs after Clostridium difficile infection. However, until now it is not known why in some patients recovered from this infection the gastrointestinal disturbances persist for months or years. Based on our in vitro studies on enteric glial cells exposed to the effects of C. difficile toxin B, we hypothesize that persistence of symptoms up to the development of irritable bowel syndrome might be due to a disturbance/impairment of the correct functions of the enteroglial intestinal network.

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The Enterotoxicity of Clostridium difficile Toxins

Cited by 93 publications

References 209 publications

In VivoPhysiological and Transcriptional Profiling Reveals Host Responses to Clostridium difficile Toxin A and Toxin B

In VivoPhysiological and Transcriptional Profiling Reveals Host Responses to Clostridium difficile Toxin A and Toxin B

Effective Sequestration of Clostridium difficile Protein Toxins by Calcium Aluminosilicate

Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum?

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