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J. Biol. Chem., Vol. 281, Issue 34, 24449-24454, August 25, 2006

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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^*

Xinhua Chen, Efi G. Kokkotou, Nasima Mustafa, K. Ramakrishnan Bhaskar, Stavros Sougioultzis, Michael O'Brien^¶, Charalabos Pothoulakis, and Ciarán P. Kelly¹

From the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, the ^¶Department of Pathology, School of Medicine, Boston University, Boston, Massachusetts 02215, and the Division of Pediatric Gastroenterology & Nutrition, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02215

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-1 in human colonocyte NCM460 cells in a dose-dependent fashion. Furthermore, SbS inhibited IL-1 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.

Received for publication, May 31, 2006

^* This work was supported by National Institutes of Health Grants P01 DK033506 and AI53069. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Gastroenterology, Dana 601A, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1272; Fax: 617-667-2767; E-mail: ckelly2{at}bidmc.harvard.edu.

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