title: Saccharomyces boulardii inhibits ERK1/2 mitogen-activated protein kinase activation both in vitro and in vivo and protects against Clostridium difficile toxin A-induced enteritis.
abstract: Saccharomyces boulardii (Sb), a probiotic yeast, protects against intestinal injury and inflammation caused by a wide variety of enteric pathogens, including Clostridium difficile. Given the broad range of protective effects of Sb in multiple gastrointestinal disorders, we hypothesize that Sb modulates host signaling pathways involved in intestinal inflammatory responses. In this study, we found that Sb culture supernatant (SbS) inhibits interleukin-8 production induced by C. difficile toxin A or IL-1beta in human colonocyte NCM460 cells in a dose-dependent fashion. Furthermore, SbS inhibited IL-1beta and toxin A induced Erk1/2 and JNK/SAPK but not p38 activation in NCM460 cells. To test whether this inhibition also occurs in vivo, we used a previously established mouse ileal loop model. On its own, SbS had no significant effect on basal fluid secretion or intestinal histology. However, Erk1/2 activation was significantly inhibited by SbS in toxin A exposed mouse ileal mucosa. In control loops, toxin A increased fluid secretion (2.2-fold), histological score (3.3-fold), and levels of the chemokine KC (4.5-fold). SbS pretreatment completely normalized toxin A mediated fluid secretion (p < 0.01), and histopathologic changes (p < 0.01) and substantially inhibited toxin A-associated KC increases (p < 0.001). In summary, the probiotic yeast S. boulardii inhibits C. difficile toxin A-associated enteritis by blocking the activation of Erk1/2 MAP kinases. This study indicates a new mechanism whereby Sb protects against intestinal inflammation and supports the hypothesis that Sb modulates host inflammatory signaling pathways to exert its beneficial effects.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Chen
authors.forename: Efi G
authors.initials: EG
authors.lastname: Kokkotou
authors.forename: Nasima
authors.initials: N
authors.lastname: Mustafa
authors.forename: K Ramakrishnan
authors.initials: KR
authors.lastname: Bhaskar
authors.forename: Stavros
authors.initials: S
authors.lastname: Sougioultzis
authors.forename: Michael
authors.initials: M
authors.lastname: O'Brien
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.forename: Ciarán P
authors.initials: CP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D002460:Cell Line; D004751:Enteritis / Q000139:chemically induced / Q000382:microbiology / Q000517:prevention & control*; D004768:Enterotoxins / Q000633:toxicity; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D019936:Probiotics; D051381:Rats; D012440:Saccharomyces / Q000502:physiology*
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3