Differential Effects of Varying Concentrations of<i>Clostridium difficile</i>Toxin A on Epithelial Barrier Function and Expression of Cytokines

Johal, S S; Solomon, Katie; Dodson, Sue; Borriello, S. P.; Mahida, Yashwant R.

doi:10.1086/386287

Cited by 57 publications

(48 citation statements)

References 37 publications

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“…For both of these cell types, significant cytotoxicity is seen only after exposure to 10 ng or more of toxin A per ml. However, at concentrations of Ͻ10 ng/ml, there is a loss of transepithelial resistance (23,34), and the cells are induced to express transforming growth factor ␤ (23). These findings support the concept that there are distinct intracellular mechanisms by which C. difficile toxin A mediates its effects on host cells (17,21,24,34,50).…”

Section: Discussionmentioning

confidence: 99%

“…Although local concentrations at the intestinal epithelial surface may not be accurately reflected by the concentrations present in a stool sample, one can postulate the in vivo significance of an in vitro response by host cells to different concentrations of the toxin. Exposure to low concentrations of toxin A induces expression of the anti-inflammatory cytokine transforming growth factor ␤ and much slower loss of epithelial barrier function (23). By contrast, high concentrations of toxin readily overcome the epithelial barrier and induce the expression of proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin-8 (14,21,38) in lamina propria monocytes/macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Monocytes Are Highly Sensitive toClostridium difficileToxin A-Induced Apoptotic and Nonapoptotic Cell Death

et al. 2005

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In this study we investigated the in vitro responses of peripheral blood mononuclear preparations and purified monocytes to Clostridium difficile toxin A. In contrast to the responses of T and B cells, exposure to toxin A led to a rapid loss of monocytes in a time-and dose-dependent fashion (the majority of cells were lost within 24 h of exposure to >100 ng of toxin per ml). Transmission electron microscopy, flow cytometry, and fluorescence microscopy after propidium iodide and Hoechst staining showed that cell death in purified preparations of monocytes following exposure to 100 and 1,000 ng of toxin A per ml occurred by apoptosis. Further studies showed that 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazole-carbocyanine iodide aggregates were retained within toxin A-exposed monocyte mitochondria, but cytochrome c was released, suggesting that the apoptotic cascade was triggered in the absence of mitochondrial permeability transition. There was also an increase in caspase-3 activity in toxin A-stimulated monocytes. Following exposure to very high concentrations of toxin A (30 g/ml), monocyte cell death was predominantly of the necrotic type, with rapid extracellular release of lactate dehydrogenase. These studies demonstrated that C. difficile toxin A has a cell-specific effect, in which monocytes exhibit greater susceptibility than lymphocytes and their death is induced in a concentration-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Monocytes Are Highly Sensitive toClostridium difficileToxin A-Induced Apoptotic and Nonapoptotic Cell Death

et al. 2005

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“…infection by one case study 16 ; and with a higher incidence of Clostridium difficile infection 17 ; whereas animal models have proven the role of specific enteric bacteria ( E. coli ENT CAI:5) in the gluten-induced immunopathology. 18 Interestingly, some of these pathogenic bacteria previosly associated with the disease can produce toxins that disrupt the tight junction proteins and increase the intestinal permeability, 19-22 a condition linked to the break-down of gluten tolerance. 1 Although some potential candidates have been proposed, we lack strong evidence for pathogenic bacteria as trigger factors for CD development in humans.…”

Section: Introductionmentioning

confidence: 99%

Increased prevalence of pathogenic bacteria in the gut microbiota of infants at risk of developing celiac disease: The PROFICEL study

et al. 2018

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Celiac disease (CD) is an immune-mediated enteropathy involving genetic and environmental factors, whose interaction influences disease risk. The intestinal microbiota, including viruses and bacteria, could play a role in the pathological process leading to gluten intolerance. In this study, we investigated the prevalence of pathogens in the intestinal microbiota of infants at familial risk of developing CD. We included 127 full-term newborns with at least one first-degree relative with CD. Infants were classified according to milk-feeding practice (breastfeeding or formula feeding) and HLA-DQ genotype (low, intermediate or high genetic risk). The prevalence of pathogenic bacteria and viruses was assessed in the faeces of the infants at 7 days, 1 month and 4 months of age. The prevalence of Clostridium perfringens was higher in formula-fed infants than in breast-fed over the study period, and that of C. difficile at 4 months. Among breastfed infants, a higher prevalence of enterotoxigenic E. coli (ETEC) was found in infants with the highest genetic risk compared either to those with a low or intermediate risk. Among formula-fed infants, a higher prevalence of ETEC was also found in infants with a high genetic risk compared to those of intermediate risk. Our results show that specific factors, such as formula feeding and the HLA-DQ2 genotype, previously linked to a higher risk of developing CD, influence the presence of pathogenic bacteria differently in the intestinal microbiota in early life. Further studies are warranted to establish whether these associations are related to CD onset later in life.

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“…In intact monolayers of carcinoma-derived intestinal epithelial cell lines in vitro, apically applied toxin A induces injury and loss of barrier function (43,45). Other early responses by intestinal epithelial cells exposed to toxin A include changes in the cytoskeleton (10,15) and secretion of cytokines, such as transforming growth factor beta (TGF-␤) (20) and interleukin-8 (5,13,26), before the cells undergo programmed cell death (6,26). Our previous studies have shown that primary human intestinal epithelial cells, monocytes, and intestinal macrophages are more sensitive than lymphocytes to C. difficile toxin A-induced cell death (25,26,42).…”

mentioning

confidence: 99%

“…In view of their capacity to secrete a number of cytokines and to interact with other cell populations (36), intestinal myofibroblasts are also believed to be key players in inflammatory responses in the intestine (1,9,12,22). They have been shown to provide protection to intestinal epithelial monolayers against loss of barrier function in response to low concentrations of toxin A, via secretion of TGF-␤ (20). Following injury and loss of toxin-exposed epithelial cells in vivo, myofibroblasts, which are capable of migrating onto the surface of the basement membrane (24), would be expected to be exposed to C. difficile toxins.…”

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confidence: 99%

Primary Human Colonic Myofibroblasts Are Resistant toClostridium difficileToxin A-Induced, but Not Toxin B-Induced, Cell Death

2011

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Colonic inflammation in Clostridium difficile infection is mediated by released toxins A and B. We investigated responses to C. difficile toxins A and B by isolated primary human colonic myofibroblasts, which represent a distinct subpopulation of mucosal cells that are normally located below the intestinal epithelium. Following incubation with either purified toxin A or B, there was a change in myofibroblast morphology to stellate cells with processes that were immunoreactive for alpha-smooth muscle actin. Most of the myofibroblasts remained viable, with persistence of stellate morphology, despite exposure to high concentrations (up to 10 g/ml) of toxin A for 72 h. In contrast, a majority of the toxin B-exposed myofibroblasts lost their processes prior to cell death over 24 to 72 h. At low concentrations, toxin A provided protection against toxin B-induced cell death. Within 4 h, myofibroblasts exposed to either toxin A or toxin B lost expression of the nonglucosylated form of Rac1, and there was also a loss of the active form of RhoA. Despite preexposure to high concentrations of toxin A for 3 h, colonic myofibroblasts were able to recover their morphology and proliferative capacity during prolonged culture in medium. However, toxin B-preexposed myofibroblasts were not able to recover. In conclusion, primary human colonic mucosal myofibroblasts are resistant to toxin A (but not toxin B)-induced cell death. Responses by colonic myofibroblasts may play an important role in mucosal protection, repair, and regeneration in colitis due to C. difficile infection.

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Differential Effects of Varying Concentrations ofClostridium difficileToxin A on Epithelial Barrier Function and Expression of Cytokines

Abstract: In C. difficile infection, the development and severity of colonic inflammation may depend on the exposure of intestinal epithelial cells to toxins and the expression of proinflammatory (IL-8) and protective (TGF-beta) factors.

Cited by 57 publications

References 37 publications

Monocytes Are Highly Sensitive toClostridium difficileToxin A-Induced Apoptotic and Nonapoptotic Cell Death

Monocytes Are Highly Sensitive toClostridium difficileToxin A-Induced Apoptotic and Nonapoptotic Cell Death

Increased prevalence of pathogenic bacteria in the gut microbiota of infants at risk of developing celiac disease: The PROFICEL study

Primary Human Colonic Myofibroblasts Are Resistant toClostridium difficileToxin A-Induced, but Not Toxin B-Induced, Cell Death

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