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Toxins
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Enterotoxins and Mucosal Pathomechanisms
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Enterotoxins and Mucosal Pathomechanisms

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 8775

Special Issue Editor

Dr. Roland Bücker

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Guest Editor
Inst. Clinical Physiology / Nutritional Medicine, Dept. Gastroenterology, Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany
Interests: gut pathogens; epithelial barrier function; tight junction regulation; clostridial toxins; bacterial pore-forming toxins and toxic metabolites; campylobacter toxins; colonization; invasion; leaky gut phenomenon; immune cell—epithelial cell co-culture and organoids; barrier-breaking mechanisms of arcobacter; aeromonas; campylobacter; clostridioides difficile; escherichia coli; klebisella oxytoca; salmonella; yersinia enterocoltitica; helicobacter pylori
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The mechanisms leading to diarrhea and inflammation in the intestinal mucosa are frequently directly caused by enterotoxins from microorganisms such as bacteria, cyanobacteria, protists, yeasts, algae or fungal toxins. Some toxins are even described to possess carcinogenic properties or genotoxic effects.

Between mild cytoskeletal alterations and rapid lethal cytotoxicity, a variety of cytopathic effects on intestinal cellular dysregulation can occur.

The topics of this Special Issue comprise insights into toxin-mediated epithelial perturbation in the gut mucosa and the inherent signaling.

Despite the description of many enterotoxins, knowledge is still lacking regarding the pathomechanisms responsible for mucosal damage and diarrhea. The diarrheal mechanisms of enterotoxins often comprise the secretory or malabsorptive type of diarrhea by the dysregulation of transporters, but also epithelial barrier dysfunction via the leak flux pathomechanism, mainly by tight junction dysregulation.

Concomitantly, the influx of noxious agents from the gut lumen can induce and aggravate mucosal inflammation, described as the leaky gut phenomenon in different inflammatory intestinal diseases. Intestinal bacterial antigens and toxins play a pivotal role in this induction of epithelial barrier dysfunction and mucosal inflammation.

Mechanisms by which toxins cross the mucosal barrier via the paracellular route or bind to cellular receptors and then take the transcellular pathway via endocytosis to gain access to subepithelial target cells can determine the outcome and contribution to mucosal disturbance, diarrhea and inflammation.

This Special Issue is open for papers on toxins from enteropathogens or pathobionts which have an impact on the intestine. We invite researchers with experimental or clinical approaches from related scientific fields such as gastroenterology, microbiology, biochemistry, physiology, epidemiology, food safety and zoonosis research and more to submit an original article or a review article to the Toxins Special Issue “Enterotoxins and Mucosal Pathomechanisms”.

Dr. Roland Bücker
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enterotoxin-producing microorganisms
  • intestinal epithelial perturbation
  • mucosal pathogenesis
  • tight junction dysregulation and epithelial permeability
  • intestinal inflammation and cytokine pathways
  • epithelial damage and genotoxic effects
  • intestinal lesions and epithelial cell death induction
  • action on cytoskeleton regulation and signaling
  • epithelial transporters and channels
  • receptor binding and cellular trafficking

Published Papers (5 papers)

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Research

19 pages, 4903 KiB  
Article
A Colonic Organoid Model Challenged with the Large Toxins of Clostridioides difficile TcdA and TcdB Exhibit Deregulated Tight Junction Proteins
by Martina Schneemann, Lucas Heils, Verena Moos, Franziska Weiß, Susanne M. Krug, January Weiner, Dieter Beule, Ralf Gerhard, Jörg-Dieter Schulzke and Roland Bücker
Toxins 2023, 15(11), 643; https://doi.org/10.3390/toxins15110643 - 04 Nov 2023
Viewed by 1590
Abstract
Background: Clostridioides difficile toxins TcdA and TcdB are responsible for diarrhea and colitis. Lack of functional studies in organoid models of the gut prompted us to elucidate the toxin’s effects on epithelial barrier function and the molecular mechanisms for diarrhea and inflammation. Methods: [...] Read more.
Background: Clostridioides difficile toxins TcdA and TcdB are responsible for diarrhea and colitis. Lack of functional studies in organoid models of the gut prompted us to elucidate the toxin’s effects on epithelial barrier function and the molecular mechanisms for diarrhea and inflammation. Methods: Human adult colon organoids were cultured on membrane inserts. Tight junction (TJ) proteins and actin cytoskeleton were analyzed for expression via Western blotting and via confocal laser-scanning microscopy for subcellular localization. Results: Polarized intestinal organoid monolayers were established from stem cell-containing colon organoids to apply toxins from the apical side and to perform functional measurements in the organoid model. The toxins caused a reduction in transepithelial electrical resistance in human colonic organoid monolayers with sublethal concentrations. Concomitantly, we detected increased paracellular permeability fluorescein and FITC-dextran-4000. Human colonic organoid monolayers exposed to the toxins exhibited redistribution of barrier-forming TJ proteins claudin-1, -4 and tricellulin, whereas channel-forming claudin-2 expression was increased. Perijunctional F-actin cytoskeleton organization was affected. Conclusions: Adult stem cell-derived human colonic organoid monolayers were applicable as a colon infection model for electrophysiological measurements. The TJ changes noted can explain the epithelial barrier dysfunction and diarrhea in patients, as well as increased entry of luminal antigens triggering inflammation. Full article
(This article belongs to the Special Issue Enterotoxins and Mucosal Pathomechanisms)
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20 pages, 4157 KiB  
Article
Protective Effects of Alginate and Chitosan Oligosaccharides against Clostridioides difficile Bacteria and Toxin
by Maria Eleni Mavrogeni, Mostafa Asadpoor, Jo H. Judernatz, Ingrid van Ark, Marc M. S. M. Wösten, Karin Strijbis, Roland J. Pieters, Gert Folkerts and Saskia Braber
Toxins 2023, 15(10), 586; https://doi.org/10.3390/toxins15100586 - 22 Sep 2023
Viewed by 1144
Abstract
Clostridioides difficile infection is expected to become the most common healthcare-associated infection worldwide. C. difficile-induced pathogenicity is significantly attributed to its enterotoxin, TcdA, which primarily targets Rho-GTPases involved in regulating cytoskeletal and tight junction (TJ) dynamics, thus leading to cytoskeleton breakdown and [...] Read more.
Clostridioides difficile infection is expected to become the most common healthcare-associated infection worldwide. C. difficile-induced pathogenicity is significantly attributed to its enterotoxin, TcdA, which primarily targets Rho-GTPases involved in regulating cytoskeletal and tight junction (TJ) dynamics, thus leading to cytoskeleton breakdown and ultimately increased intestinal permeability. This study investigated whether two non-digestible oligosaccharides (NDOs), alginate (AOS) and chitosan (COS) oligosaccharides, possess antipathogenic and barrier-protective properties against C. difficile bacteria and TcdA toxin, respectively. Both NDOs significantly reduced C. difficile growth, while cell cytotoxicity assays demonstrated that neither COS nor AOS significantly attenuated the TcdA-induced cell death 24 h post-exposure. The challenge of Caco-2 monolayers with increasing TcdA concentrations increased paracellular permeability, as measured by TEER and LY flux assays. In this experimental setup, COS completely abolished, and AOS mitigated, the deleterious effects of TcdA on the monolayer’s integrity. These events were not accompanied by alterations in ZO-1 and occludin protein levels; however, immunofluorescence microscopy revealed that both AOS and COS prevented the TcdA-induced occludin mislocalization. Finally, both NDOs accelerated TJ reassembly upon a calcium-switch assay. Overall, this study established the antipathogenic and barrier-protective capacity of AOS and COS against C. difficile and its toxin, TcdA, while revealing their ability to promote TJ reassembly in Caco-2 cells. Full article
(This article belongs to the Special Issue Enterotoxins and Mucosal Pathomechanisms)
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18 pages, 4481 KiB  
Article
Bacteroides fragilis Enterotoxin Induces Autophagy through an AMPK and FoxO3-Pathway, Leading to the Inhibition of Apoptosis in Intestinal Epithelial Cells
by Su Hyuk Ko, Jun Ho Choi and Jung Mogg Kim
Toxins 2023, 15(9), 544; https://doi.org/10.3390/toxins15090544 - 03 Sep 2023
Cited by 2 | Viewed by 1118
Abstract
Macroautophagy/autophagy is essential for preserving cellular homeostasis by recycling nutrients and removing spoiled or aged proteins and organelles. It also has an essential role in defense mechanisms against microbial infections. However, the role of autophagy in enterotoxigenic Bacteroides fragilis infection remains largely unknown. [...] Read more.
Macroautophagy/autophagy is essential for preserving cellular homeostasis by recycling nutrients and removing spoiled or aged proteins and organelles. It also has an essential role in defense mechanisms against microbial infections. However, the role of autophagy in enterotoxigenic Bacteroides fragilis infection remains largely unknown. In this study, we explored the role of B. fragilis enterotoxin (BFT) in the autophagic process of intestinal epithelial cells (IECs). The LC3-I of human HCT-116 IECs was converted to LC3-II by BFT stimulation. In addition, BFT-exposed cells showed the decreased expression of p62 in a time-dependent manner and increased levels of ATG5 and ATG12 gradually. Evidence of an enhanced autophagic process was supported by autophagosomes co-localized with LC3-lysosome-associated protein 2 in BFT-stimulated cells. The AMP-activated protein kinase (AMPK) and Forkhead box O3 (FoxO3a) axis were required for BFT-induced autophagy activation. In contrast with the activation of autophagy at 3–6 h after BFT exposure, IECs induced apoptosis-related signals at 12–48 h. HCT-116 IECs suppressing the formation of autophagosomes significantly activated apoptosis signals instead of autophagy early after BFT exposure. These data suggest that BFT can activate autophagy through the AMPK-FoxO3a pathway and the autophagy may suppress apoptosis during early exposure of IECs to BFT. Full article
(This article belongs to the Special Issue Enterotoxins and Mucosal Pathomechanisms)
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10 pages, 3424 KiB  
Article
Molecular Basis of TcdR-Dependent Promoter Activity for Toxin Production by Clostridioides difficile Studied by a Heterologous Reporter System
by Xinyue Zhang, Jie Li, Chao Chen, Ya-Jun Liu, Qiu Cui, Wei Hong, Zhenghong Chen, Yingang Feng and Guzhen Cui
Toxins 2023, 15(5), 306; https://doi.org/10.3390/toxins15050306 - 23 Apr 2023
Cited by 2 | Viewed by 1681
Abstract
The alternative σ factor TcdR controls the synthesis of two major enterotoxins: TcdA and TcdB in Clostridioides difficile. Four potential TcdR-dependent promoters in the pathogenicity locus of C. difficile showed different activities. In this study, we constructed a heterologous system in Bacillus [...] Read more.
The alternative σ factor TcdR controls the synthesis of two major enterotoxins: TcdA and TcdB in Clostridioides difficile. Four potential TcdR-dependent promoters in the pathogenicity locus of C. difficile showed different activities. In this study, we constructed a heterologous system in Bacillus subtilis to investigate the molecular basis of TcdR-dependent promoter activity. The promoters of the two major enterotoxins showed strong TcdR-dependent activity, while the two putative TcdR-dependent promoters in the upstream region of the tcdR gene did not show detectable activity, suggesting that the autoregulation of TcdR may need other unknown factors involved. Mutation analysis indicated that the divergent -10 region is the key determinant for different activities of the TcdR-dependent promoters. Analysis of the TcdR model predicted by AlphaFold2 suggested that TcdR should be classified into group 4, i.e., extracytoplasmic function, σ70 factors. The results of this study provide the molecular basis of the TcdR-dependent promoter recognition for toxin production. This study also suggests the feasibility of the heterologous system in analyzing σ factor functions and possibly in drug development targeting these factors. Full article
(This article belongs to the Special Issue Enterotoxins and Mucosal Pathomechanisms)
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15 pages, 3925 KiB  
Article
CDT of Clostridioides difficile Induces MLC-Dependent Intestinal Barrier Dysfunction in HT-29/B6 Epithelial Cell Monolayers
by Lucas Heils, Martina Schneemann, Ralf Gerhard, Jörg-Dieter Schulzke and Roland Bücker
Toxins 2023, 15(1), 54; https://doi.org/10.3390/toxins15010054 - 07 Jan 2023
Cited by 2 | Viewed by 2403
Abstract
Background: Clostridioides difficile binary toxin (CDT) defines the hypervirulence of strains in nosocomial antibiotic-induced colitis with the highest mortality. The objective of our study was to investigate the impact of CDT on the intestinal epithelial barrier and to enlighten the underlying molecular mechanisms. Methods: [...] Read more.
Background: Clostridioides difficile binary toxin (CDT) defines the hypervirulence of strains in nosocomial antibiotic-induced colitis with the highest mortality. The objective of our study was to investigate the impact of CDT on the intestinal epithelial barrier and to enlighten the underlying molecular mechanisms. Methods: Functional measurements of epithelial barrier function by macromolecular permeability and electrophysiology were performed in human intestinal HT-29/B6 cell monolayers. Molecular analysis of the spatial distribution of tight junction protein and cytoskeleton was performed by super-resolution STED microscopy. Results: Sublethal concentrations of CDT-induced barrier dysfunction with decreased TER and increased permeability for 332 Da fluorescein and 4 kDa FITC-dextran. The molecular correlate to the functional barrier defect by CDT was found to be a tight junction protein subcellular redistribution with tricellulin, occludin, and claudin-4 off the tight junction domain. This redistribution was shown to be MLCK-dependent. Conclusions: CDT compromised epithelial barrier function in a human intestinal colonic cell model, even in sublethal concentrations, pointing to barrier dysfunction in the intestine and leak flux induction as a diarrheal mechanism. However, this cannot be attributed to the appearance of apoptosis and necrosis, but rather to an opening of the paracellular leak pathway as the result of epithelial tight junction alterations. Full article
(This article belongs to the Special Issue Enterotoxins and Mucosal Pathomechanisms)
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