Proinflammatory Cytokines: Possible Accomplices for the Systemic Effects of Clostridioides difficile Toxin B

Katia Fettucciari,1 Alessandro Fruganti,2 Andrea Marchegiani,2 Stefano Brancorsini,1 Pierfrancesco Marconi,1 Gabrio Bassotti3,4 1Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy; 2School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy; 3Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy; 4Gastroenterology & Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, ItalyCorrespondence: Katia FettucciariDepartment of Experimental Medicine, University of Perugia Medical School, Piazza Lucio Severi 1, Edificio B IV Piano, Sant’Andrea delle Fratte, Perugia 06132, ItalyTel +39755858124Email katia.fettucciari@unipg.itAbstract: Clostridioides difficile infection (CDI) has a serious impact on the healthcare system, and most of its pathogenic effects are mainly due to the activity of toxins A and B (TcdA and TcdB, respectively). The molecular mechanisms of their cytotoxic activity are well known, especially in the colon, where the infection occurs and normally remains localized. However, the mechanisms causing toxic effects on various systemic organs (extraintestinal manifestations) with frequent lethal outcomes in some patients affected by CDI are still poorly understood. Few studies are available that demonstrate low serum levels of Tcds in both experimental animal models and patients with CDI. Until now, it has remained unclear how low levels of circulating Tcds could lead to serious toxic effects. On the basis of our previous in vitro studies, in which the proinflammatory cytokines TNF-alpha and IFN-gamma strongly potentiated the toxic activity of low doses of TcdB, we hypothesize that the presence of both TcdB in the circulation and a systemic proinflammatory cytokine storm may be responsible for the selective severe effects of TcdB in some patients. This may occur in patients with severe CDI and systemic Tcds, in whom proinflammatory cytokines such as TNF-alpha and IFN-gamma reach a significant concentration in the circulation. This hypothesis could identify therapeutic interventions based on the reduction or neutralization of the indirect toxic action of these cytokines.Keywords: Clostridioides difficile, toxin B, proinflammatory cytokines, TNF-alpha, IFN-gamma, systemic effects