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Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2023; 29(4): 582-596
Published online Jan 28, 2023. doi: 10.3748/wjg.v29.i4.582
Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases
Gabrio Bassotti, Alessandro Fruganti, Fabrizio Stracci, Pierfrancesco Marconi, Katia Fettucciari
Gabrio Bassotti, Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section University of Perugia Medical School, Piazza Lucio Severi, Perugia 06132, Italy, and Santa Maria della Misericordia Hospital, Gastroenterology & Hepatology Unit Perugia 06156, Italy
Alessandro Fruganti, School of Biosciences and Veterinary Medicine, University of Camerino, Matelica 62024, Italy
Fabrizio Stracci, Medicine and Surgery, Hygiene and Public Health Section, University of Perugia, Perugia 06123, Italy
Pierfrancesco Marconi, Katia Fettucciari, Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia 06132, Italy
Author contributions: Bassotti G organized the project and contributed to finalizing the draft; Fruganti A, Stracci F, and Marconi P critically revised the manuscript; Fettucciari K wrote the draft and contributed to finalizing it; All authors approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest to report.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gabrio Bassotti, MD, PhD, Associate Professor, Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section University of Perugia Medical School, Piazza Lucio Severi, Perugia 06132, Italy, and Santa Maria della Misericordia Hospital, Gastroenterology & Hepatology Unit Perugia 06156, Italy. gabassot@tin.it
Received: September 15, 2022
Peer-review started: September 15, 2022
First decision: November 26, 2022
Revised: December 3, 2022
Accepted: December 27, 2022
Article in press: December 27, 2022
Published online: January 28, 2023
Processing time: 127 Days and 2.5 Hours
Abstract

Clostridioides difficile (C. difficile) is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of C. difficile (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by C. difficile becomes a risk after the use of antibiotics that alter the microbiome, other categories of people are more susceptible to infection and at risk of relapse, such as those with inflammatory bowel disease (IBD). Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma (CKs). Therefore, in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C. difficile infection and its progression and relapses. TcdB is internalized in the cell via three receptors: chondroitin sulphate proteoglycan 4; poliovirus receptor-like 3; and Wnt receptor frizzled family. Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types, while poliovirus receptor-like 3 induces only necrosis. It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis. Therefore, in subjects with IBD there are the conditions: (1) For greater susceptibility to C. difficile infection, such as the inflammatory state, and abnormalities of the microbiome and of the immune system; (2) for the enhancement of the cytotoxic activity of TcdB +Cks; and (3) for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis. The only therapeutic approach currently possible in IBD patients is monitoring of C. difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins. The future perspective is to generate bacteriophages against C. difficile for targeted therapy.

Keywords: Inflammatory bowel diseases; Clostridioides difficile infection; Cytokines; Tumor necrosis factor-alpha; Interferon-gamma; Necrosis; Apoptosis; Cytotoxic synergism

Core Tip: Clostridioides difficile is an opportunistic pathogen that is progressively increasing worldwide. Patients with inflammatory bowel diseases are particularly susceptible due to altered immunological status and the therapies adopted that favor intestinal dysbiosis and colonization by Clostridioides difficile. Recent in vitro studies also suggest that the infection might be favored by the strong cytotoxic synergism between Clostridioides difficile toxin B and proinflammatory cytokines, thetumor necrosis factor-alpha and interferon-gamma. The therapeutic approaches are still limited, and those presently available rely on antibiotic therapy and fecal transplantation.