In Colon Epithelia, Clostridium perfringens Enterotoxin Causes Focal Leaks by Targeting Claudins Which are Apically Accessible Due to Tight Junction Derangement

Abstract

Clostridium perfringens enterotoxin (CPE) causes food poisoning and antibiotic-associated diarrhea. It uses some claudin tight junction proteins (eg, claudin-4) as receptors to form Ca2+-permeable pores in the membrane, damaging epithelial cells in small intestine and colon. We demonstrate that only a subpopulation of colonic enterocytes which are characterized by apical dislocation of claudins are CPE-susceptible. CPE-mediated damage was enhanced if paracellular barrier was impaired by Ca2+ depletion, proinflammatory cytokine tumor necrosis factor α, or dedifferentiation. Microscopy, Ca2+ monitoring, and electrophysiological data showed that CPE-mediated cytotoxicity and barrier disruption was limited by extent of CPE-binding. The latter was restricted by accessibility of non-junctional claudin molecules such as claudin-4 at apical membranes. Focal-leaks detected in HT-29/B6 colonic monolayers were verified for native tissue using colon biopsies. These mechanistic findings indicate how CPE-mediated effects may turn from self-limiting diarrhea into severe clinical manifestation such as colonic necrosis-if intestinal barrier dysfunction, eg, during inflammation facilitates claudin accessibility.

Targeting claudin‐overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin

“…However, use of CPE for tumor therapy is restricted by the fact that CPE‐binding claudins are expressed in numerous tissues and, thereby, there is risk of unwanted cytotoxic damage of normal cells. Nevertheless, most tumor cells are assumed to be more sensitive to CPE than differentiated epithelial cells due to (a) overexpression and (b) higher accessibility of claudins caused by extrajunctional mislocalization of the molecules (Corsini et al , ; Eichner et al , ) (Fig. ).…”

An update on the human and animal enteric pathogen Clostridium perfringens

“…CPE (encoding gene cpe ) is recognised as the key toxin to cause food-poisoning and non-foodborne diarrhoea, it has also been demonstrated to disrupt the intercellular claudin tight junctions in gut epithelial cells 68 , 69 . Importantly, this pore-forming toxin was demonstrated to bind and necrotise human ileal and colonic epithelium in vitro, and can induce cell death i.e., apoptosis, via the caspase-3 pathway 70 .…”

The “Leaky Gut”: Tight Junctions but Loose Associations?

“…Though the normal intestinal microbiome does not include large amounts of pathogenic organisms, as an example, increased proliferation of the pathogen Clostridium botulinum is associated with release of botulinum neurotoxins, damaging the intestinal barrier and fostering absorption of the neurotoxin into the systemic circulation and the nervous system, causing botulism [49]. Furthermore, the exotoxins of diarrheagenic toxin-producing bacteria such as Clostridium perfringens, Salmonella typhimurium, Shigella flexneri, Vibrio cholerae, and toxigenic E. coli specifically bind to and alter the function of tight junctions, with consequent massive fluid and electrolyte secretion [81,82].…”