Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

• Published in: World journal of gastroenterology : WJG 2023-01, Vol.29 (4), p.582-596
• Main Authors: Bassotti, Gabrio, Fruganti, Alessandro, Stracci, Fabrizio, Marconi, Pierfrancesco, Fettucciari, Katia
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents; Bacterial Proteins - metabolism; Bacterial Toxins; Clostridioides difficile; Clostridium Infections; Cytokines - metabolism; Enterotoxins; Humans; Inflammatory Bowel Diseases - drug therapy; Interferon-gamma - metabolism; Necrosis; Receptors, Wnt - metabolism; Review; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v29.i4.582

( ) is progressively colonizing humans and animals living with humans. During this process, hypervirulent strains and mutated toxin A and B of (TcdA and TcdB) are originating and developing. While in healthy subjects colonization by 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 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 infection and its progression and relapses. TcdB is internalized in the cell 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 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 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 for targeted therapy.