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Gabrio Bassotti,1,2 Alessandro Fruganti,3 Giovanni Maconi,4 Pierfrancesco Marconi,5 Katia Fettucciari5 1Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section, University of Perugia, Perugia, Italy; 2Gastroenterology & Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, Italy; 3School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy; 4Department of Biomedical and Clinical Sciences, Gastroenterology Unit, “L. Sacco” Hospital, University of Milano, Milano, Italy; 5Department of Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia, ItalyCorrespondence: Gabrio BassottiDepartment of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section, University of Perugia, Perugia, ItalyEmail gabassot@tin.itAbstract: Clostridioides difficile infection is widespread throughout countries and represents an important cause of nosocomial diarrhoea, with relatively high morbidity. This infection often occurs in patients with inflammatory bowel diseases and may complicate their clinical picture. Here, we propose, on the basis of evidence from basic science studies, that in patients affected by inflammatory bowel diseases, this infection might be facilitated by a derangement of the enteric glial cell (EGC) network caused by the effects of proinflammatory cytokines, such as tumour necrosis factor alpha and interferon gamma, which enhance the cytotoxic effects of C. difficile toxin B on EGCs. This hypothesis, if confirmed, could open the door to alternative treatment approaches to fight C. difficile infection.Keywords: Clostridioides difficile infection, cytokines, inflammatory bowel diseases, interferon gamma, tumour necrosis factor alpha

Gabrio Bassotti,1 Paolo Usai Satta,2 Massimo Bellini3 1Gastroenterology & Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy; 2Gastrointestinal Unit, “G. Brotzu” Hospital, Cagliari, Italy; 3Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyCorrespondence: Gabrio BassottiClinica di Gastroenterologia ed Epatologia, Ospedale Santa Maria della Misericordia, Piazzale Menghini, 1, San Sisto (Perugia), 06156, ItalyEmail gabassot@tin.itAbstract: Chronic idiopathic constipation (CIC) is a common functional bowel disorder characterized by difficult, infrequent, and/or incomplete defecation. It has a great impact on the quality of life and on health care system and represents a heavy economic burden. The diagnosis is based on symptoms, classified by the Rome IV criteria. The aim of this review was to evaluate the current therapeutic guidelines for adult CIC and highlight new emerging treatments. In detail, European, French, Spanish and Korean guidelines have been identified and compared. Osmotic laxatives, and in particular polyethylene glycol, represent the first-line therapeutic approach. Stimulant laxatives are recommended as a second-line therapy. Pelvic floor rehabilitation is recommended in patients with ano-rectal dyssynergia. In patients who fail to improve with pharmacological therapies sacral nerve stimulation is considered as last chance before surgery. Surgical approach has however limited indications in selected cases. Inertia coli refractory to any approach and obstructed defecation are two subtypes which can benefit from surgery. Among emerging agents, prucalopride, a prokinetic agent, is recommended as a second-line treatment in refractory CIC patients. In addition, the secretagogues linaclotide and plecanatide and the bile acid transported inhibitor elobixibat can be effective in patients not responsive to a second-line therapeutic regimen, although they are not worldwide commercially available.Keywords: chronic idiopathic constipation, guidelines, osmotic laxatives, pelvic floor rehabilitation, prokinetics, secretagogues

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

Small bowel manometry can play a valuable role in obtaining reliable information about gut reactions. In this way, it can be established whether people who believe that they are suffering from food hypersensitivity have genuine physical problems. Manometry can identify intestinal dysmotilities linked with the ingestion of foods which are believed to produce allergic reactions or intolerances. However, it is important to adopt a multidisciplinary approach to the diagnosis and treatment of food intolerances.