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
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-1β in human colonocyte NCM460 cells in a dose-dependent fashion. Furthermore, SbS inhibited IL-1β 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. 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-1β in human colonocyte NCM460 cells in a dose-dependent fashion. Furthermore, SbS inhibited IL-1β 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. Clostridium difficile causes antibiotic-associated diarrhea and colitis in animals and humans (1Bartlett J.G. Chang T.W. Gurwith M. Gorbach S.L. Onderdonk A.B. N. Engl. J. Med. 1978; 298: 531-534Crossref PubMed Scopus (1013) Google Scholar) and is one of the most common nosocomial infections (2McFarland L.V. Mulligan M.E. Kwok R.Y. Stamm W.E. N. Engl. J. Med. 1989; 320: 204-210Crossref PubMed Scopus (1144) Google Scholar). Toxin A, a 308-kDa protein (3Dove C.H. Wang S.Z. Price S.B. Phelps C.J. Lyerly D.M. Wilkins T.D. Johnson J.L. Infect. Immun. 1990; 58: 480-488Crossref PubMed Google Scholar), is a major virulence factor of C. difficile (4Kelly C.P. Pothoulakis C. LaMont N. Engl. J. Med. PubMed Scopus Google Scholar). we that in human used Saccharomyces Sb used Saccharomyces Sb and p38 MAP by C. difficile toxin A and and M. S. S. Pothoulakis C. LaMont C.P. J. PubMed Scopus Google Scholar). of toxin A causes fluid increased and and of inflammatory J. S. 1990; PubMed Scopus Google Pothoulakis C. LaMont PubMed Scopus Google Pothoulakis C. C. 1989; PubMed Scopus Google yeast Saccharomyces boulardii used a probiotic to or a wide variety of human gastrointestinal disorders, including antibiotic-associated diarrhea and C. difficile diarrhea and colitis L.V. J. Med. PubMed Google J. PubMed Scopus Google Scholar). Sb also in in M. M. PubMed Scopus Google Scholar). However, the whereby Sb its beneficial effects not that Sb multiple its protective effects Infect. PubMed Scopus Google Scholar). inhibition of J. PubMed Scopus Google Scholar), of PubMed Scopus Google S. Infect. Immun. PubMed Scopus Google Scholar), of virulence C. C.P. N. C.J. PubMed Google PubMed Google Scholar), and of the PubMed Scopus Google C. 1990; PubMed Scopus Google S. M. Pothoulakis C. LaMont C.P. Infect. Immun. PubMed Scopus Google Scholar). intestinal inflammation is a common of C. difficile caused by human enteric pathogens, and the beneficial effects of S. boulardii to hypothesize that this probiotic yeast of host signaling pathways that the intestinal inflammatory To study we the effect of Sb on MAP signaling in human cells in in mouse ileal in and cells NCM460 in and in a in a Toxin A was to C. difficile previously C. LaMont N. J. PubMed Scopus Google Scholar). human IL-1β was against MAP and against MAP of S. boulardii Sb was by and was in culture in was and the supernatant supernatant was a to yeast cells. and previously that Sb C. C.P. N. C.J. PubMed Google LaMont Pothoulakis C. Infect. Immun. PubMed Google Pothoulakis C. Infect. Immun. PubMed Google PubMed Scopus Google Scholar). To we the supernatant a was Sb supernatant protein levels by previously S. S. C.P. J. PubMed Scopus Google Scholar). In of to and was a of SbS in the supernatant not the S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). cells Toxin A or human IL-1β in the or of SbS cells in a and of by and in in and against and and was by and the of the was by to A a of and in of a of of A was and one to loop was the previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). ileal of SbS or of of toxin A or was and animals on a the of the and animals by and toxin A the animals and fluid secretion was the loop M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). in and and and and of the ileal was by a in a a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). levels of the chemokine KC by a by the and the of test used by IL-1β or C. difficile Toxin a human colonocyte and human IL-1β or toxin A in the or of of the and protein levels by in NCM460 cells protein IL-1β or toxin A increased protein of SbS significantly production in toxin A or NCM460 in a dose-dependent Erk1/2 and JNK/SAPK but p38 in NCM460 and production in to and the of in IL-1β induced and p38 in NCM460 cells of SbS inhibited activation of Erk1/2 and JNK/SAPK but had no effect on p38 of MAP activation by NCM460 and IL-1β in the or of SbS and and protein was on and against and of Toxin Erk1/2 and JNK/SAPK but p38 in NCM460 we that C. difficile toxin A MAP in cells. of p38 MAP by toxin A in also However, the of toxin A to or MAP in human not in toxin A induced and p38 SbS inhibited Erk1/2 and activation induced by toxin A but had no significant effect on p38 of C. difficile toxin A induced MAP activation by NCM460 and toxin A in the or of SbS and and protein was on and against and of was of Erk1/2 by Toxin A in of pretreatment SbS or toxin A and mouse loop on and the of MAP kinases. in toxin A induced activation in and toxin SbS pretreatment significantly inhibited that activation the and (p < was activation by toxin Toxin A also increased JNK/SAPK activation in ileal and this was by SbS pretreatment was no significant in JNK/SAPK activation the and SbS had no effect on p38 activation of the we in in of SbS on Erk1/2 activation in toxin mouse ileal ileal in the of and SbS or to toxin A or and ileal and on and Erk1/2 or one of one mouse of of the of indicates < toxin A of SbS on JNK/SAPK and p38 activation in toxin A mouse ileal ileal in the of and to toxin A or and ileal and on and or of indicates < toxin A against Toxin and KC in loops, toxin A increased fluid secretion by by the loop control SbS inhibited this effect of toxin A toxin A, toxin A < SbS no effect on fluid secretion inhibited toxin fluid secretion of mouse ileal ileal in the of and of SbS or of toxin A or was and animals on a the of the toxin A animals and fluid secretion was the loop toxin A, toxin A < indicates < toxin A of histological in mouse ileal and and a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). in toxin A caused a in the histological injury score SbS against this histological injury toxin A, toxin A < against histological caused by toxin ileal in in and and and and of and by a in a a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). toxin A, toxin A < indicates < toxin A we found that SbS inhibited toxin A induced chemokine secretion in human we levels of the chemokine the mouse of in mouse ileal in toxin A increased KC in the ileal by of the ileal SbS toxin KC SbS not KC toxin A, toxin A < inhibited the in ileal KC levels in to toxin levels of the chemokine KC by in the toxin A and SbS toxin A, toxin A < indicates < toxin A difficile is a a variety of gastrointestinal including antibiotic-associated diarrhea and colitis (4Kelly C.P. Pothoulakis C. LaMont N. Engl. J. Med. PubMed Scopus Google Scholar). S. boulardii used and in of to against intestinal and secretion caused by a wide variety of enteric including C. difficile L.V. J. Med. PubMed Google J. PubMed Scopus Google Scholar). In a S. boulardii was also in in M. M. PubMed Scopus Google and the protective and effects of probiotic S. boulardii in enteric infections and in inflammatory in humans not beneficial effects of S. boulardii to hypothesize that this probiotic yeast of host signaling pathways that intestinal and that S. boulardii its in by host MAP signaling in and in that S. boulardii inhibited production induced by IL-1β or toxin A in a dose-dependent that the effect of SbS is and not of or protein production S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). is that MAP production in to or S. M. PubMed Scopus Google J. Google Scholar) C. difficile toxin A M. S. S. Pothoulakis C. LaMont C.P. J. PubMed Scopus Google Scholar). that the activation of Erk1/2 and JNK/SAPK by IL-1β and toxin A inhibited by the of SbS in human and SbS also significantly inhibits Erk1/2 activation in toxin mouse ileal A effect is JNK/SAPK activation but is significant to toxin A SbS not the activation of p38 in NCM460 cells by IL-1β or toxin A and p38 activation in the in mouse ileal loop used of ileal the that we the of not intestinal cells. the of SbS inhibition of activation on MAP in its effect in NCM460 cells in inhibition of Erk1/2 activation and no significant effect on p38 MAP that or J. PubMed Scopus Google J. PubMed Scopus Google S. J.L. PubMed Scopus Google Scholar), this that the of SbS is involved Erk1/2 and JNK/SAPK and or not we that Sb also inhibited or production human cells and cells S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). a by S. Infect. Immun. PubMed Scopus Google Scholar) that the of S. boulardii yeast to human and MAP activation study S. boulardii and of human cells to Chang Chang J. Google Scholar). the hypothesis that S. boulardii is of host signaling of C. difficile toxin A this S. Infect. Immun. PubMed Scopus Google Scholar), or S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). This effect on host signaling S. boulardii effects on a wide variety of gastrointestinal whereby S. boulardii host signaling is not to this probiotic to host signaling that intestinal is of S. and of and inhibits the activation of the in intestinal cells C. Chang PubMed Scopus Google Scholar). also that inhibits activation of the p38 MAP by or but no effect on the J. PubMed Scopus Google Scholar). the that beneficial effects of in enteric mediated of host or intestinal to the of the gastrointestinal PubMed Scopus Google Scholar). of the probiotic of the intestinal to the of effect of probiotic the of and inflammatory Clostridium difficile causes antibiotic-associated diarrhea and colitis in animals and humans (1Bartlett J.G. Chang T.W. Gurwith M. Gorbach S.L. Onderdonk A.B. N. Engl. J. Med. 1978; 298: 531-534Crossref PubMed Scopus (1013) Google Scholar) and is one of the most common nosocomial infections (2McFarland L.V. Mulligan M.E. Kwok R.Y. Stamm W.E. N. Engl. J. Med. 1989; 320: 204-210Crossref PubMed Scopus (1144) Google Scholar). Toxin A, a 308-kDa protein (3Dove C.H. Wang S.Z. Price S.B. Phelps C.J. Lyerly D.M. Wilkins T.D. Johnson J.L. Infect. Immun. 1990; 58: 480-488Crossref PubMed Google Scholar), is a major virulence factor of C. difficile (4Kelly C.P. Pothoulakis C. LaMont N. Engl. J. Med. PubMed Scopus Google Scholar). we that in human used Saccharomyces Sb used Saccharomyces Sb and p38 MAP by C. difficile toxin A and and M. S. S. Pothoulakis C. LaMont C.P. J. PubMed Scopus Google Scholar). of toxin A causes fluid increased and and of inflammatory J. S. 1990; PubMed Scopus Google Pothoulakis C. LaMont PubMed Scopus Google Pothoulakis C. C. 1989; PubMed Scopus Google Scholar). yeast Saccharomyces boulardii used a probiotic to or a wide variety of human gastrointestinal disorders, including antibiotic-associated diarrhea and C. difficile diarrhea and colitis L.V. J. Med. PubMed Google J. PubMed Scopus Google Scholar). Sb also in in M. M. PubMed Scopus Google Scholar). However, the whereby Sb its beneficial effects not that Sb multiple its protective effects Infect. PubMed Scopus Google Scholar). inhibition of J. PubMed Scopus Google Scholar), of PubMed Scopus Google S. Infect. Immun. PubMed Scopus Google Scholar), of virulence C. C.P. N. C.J. PubMed Google PubMed Google Scholar), and of the PubMed Scopus Google C. 1990; PubMed Scopus Google S. M. Pothoulakis C. LaMont C.P. Infect. Immun. PubMed Scopus Google Scholar). intestinal inflammation is a common of C. difficile caused by human enteric pathogens, and the beneficial effects of S. boulardii to hypothesize that this probiotic yeast of host signaling pathways that the intestinal inflammatory To study we the effect of Sb on MAP signaling in human cells in in mouse ileal in and cells NCM460 in and in a in a Toxin A was to C. difficile previously C. LaMont N. J. PubMed Scopus Google Scholar). human IL-1β was against MAP and against MAP of S. boulardii Sb was by and was in culture in was and the supernatant supernatant was a to yeast cells. and previously that Sb C. C.P. N. C.J. PubMed Google LaMont Pothoulakis C. Infect. Immun. PubMed Google Pothoulakis C. Infect. Immun. PubMed Google PubMed Scopus Google Scholar). To we the supernatant a was Sb supernatant protein levels by previously S. S. C.P. J. PubMed Scopus Google Scholar). In of to and was a of SbS in the supernatant not the S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). cells Toxin A or human IL-1β in the or of SbS cells in a and of by and in in and against and and was by and the of the was by to A a of and in of a of of A was and one to loop was the previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). ileal of SbS or of of toxin A or was and animals on a the of the and animals by and toxin A the animals and fluid secretion was the loop M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). in and and and and of the ileal was by a in a a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). levels of the chemokine KC by a by the and the of test used and cells NCM460 in and in a in a Toxin A was to C. difficile previously C. LaMont N. J. PubMed Scopus Google Scholar). human IL-1β was against MAP and against MAP of S. boulardii Sb was by and was in culture in was and the supernatant supernatant was a to yeast cells. and previously that Sb C. C.P. N. C.J. PubMed Google LaMont Pothoulakis C. Infect. Immun. PubMed Google Pothoulakis C. Infect. Immun. PubMed Google PubMed Scopus Google Scholar). To we the supernatant a was Sb supernatant protein levels by previously S. S. C.P. J. PubMed Scopus Google Scholar). In of to and was a of SbS in the supernatant not the S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). cells Toxin A or human IL-1β in the or of SbS cells in a and of by and in in and against and and was by and the of the was by to Toxin A a of and in of a of of A was and one to loop was the previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). ileal of SbS or of of toxin A or was and animals on a the of the and animals by and toxin A the animals and fluid secretion was the loop M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). in and and and and of the ileal was by a in a a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). levels of the chemokine KC by a by the and the of test used by IL-1β or C. difficile Toxin a human colonocyte and human IL-1β or toxin A in the or of of the and protein levels by in NCM460 cells protein IL-1β or toxin A increased protein of SbS significantly production in toxin A or NCM460 in a dose-dependent Erk1/2 and JNK/SAPK but p38 in NCM460 and production in to and the of in IL-1β induced and p38 in NCM460 cells of SbS inhibited activation of Erk1/2 and JNK/SAPK but had no effect on p38 Toxin Erk1/2 and JNK/SAPK but p38 in NCM460 we that C. difficile toxin A MAP in cells. of p38 MAP by toxin A in also However, the of toxin A to or MAP in human not in toxin A induced and p38 SbS inhibited Erk1/2 and activation induced by toxin A but had no significant effect on p38 of C. difficile toxin A induced MAP activation by NCM460 and toxin A in the or of SbS and and protein was on and against and of was of Erk1/2 by Toxin A in of pretreatment SbS or toxin A and mouse loop on and the of MAP kinases. in toxin A induced activation in and toxin SbS pretreatment significantly inhibited that activation the and (p < was activation by toxin Toxin A also increased JNK/SAPK activation in ileal and this was by SbS pretreatment was no significant in JNK/SAPK activation the and SbS had no effect on p38 activation of the we in in of SbS on Erk1/2 activation in toxin mouse ileal ileal in the of and SbS or to toxin A or and ileal and on and Erk1/2 or one of one mouse of of the of indicates < toxin A of SbS on JNK/SAPK and p38 activation in toxin A mouse ileal ileal in the of and to toxin A or and ileal and on and or of indicates < toxin A against Toxin and KC in loops, toxin A increased fluid secretion by by the loop control SbS inhibited this effect of toxin A toxin A, toxin A < SbS no effect on fluid secretion inhibited toxin fluid secretion of mouse ileal ileal in the of and of SbS or of toxin A or was and animals on a the of the toxin A animals and fluid secretion was the loop toxin A, toxin A < indicates < toxin A of histological in mouse ileal and and a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). in toxin A caused a in the histological injury score SbS against this histological injury toxin A, toxin A < against histological caused by toxin ileal in in and and and and of and by a in a a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). toxin A, toxin A < indicates < toxin A we found that SbS inhibited toxin A induced chemokine secretion in human we levels of the chemokine the mouse of in mouse ileal in toxin A increased KC in the ileal by of the ileal SbS toxin KC SbS not KC toxin A, toxin A < inhibited the in ileal KC levels in to toxin levels of the chemokine KC by in the toxin A and SbS toxin A, toxin A < indicates < toxin A SbS by IL-1β or C. difficile Toxin a human colonocyte and human IL-1β or toxin A in the or of of the and protein levels by in NCM460 cells protein IL-1β or toxin A increased protein of SbS significantly production in toxin A or NCM460 in a dose-dependent fashion. SbS Erk1/2 and JNK/SAPK but p38 in NCM460 and production in to and the of in IL-1β induced and p38 in NCM460 cells of SbS inhibited activation of Erk1/2 and JNK/SAPK but had no effect on p38 SbS Toxin Erk1/2 and JNK/SAPK but p38 in NCM460 we that C. difficile toxin A MAP in cells. of p38 MAP by toxin A in also However, the of toxin A to or MAP in human not in toxin A induced and p38 SbS inhibited Erk1/2 and activation induced by toxin A but had no significant effect on p38 SbS of Erk1/2 by Toxin A in of pretreatment SbS or toxin A and mouse loop on and the of MAP kinases. in toxin A induced activation in and toxin SbS pretreatment significantly inhibited that activation the and (p < was activation by toxin Toxin A also increased JNK/SAPK activation in ileal and this was by SbS pretreatment was no significant in JNK/SAPK activation the and SbS had no effect on p38 activation of the we in in SbS against Toxin and KC in loops, toxin A increased fluid secretion by by the loop control SbS inhibited this effect of toxin A toxin A, toxin A < SbS no effect on fluid secretion of histological in mouse ileal and and a previously M. S. C. Pothoulakis C. J. PubMed Scopus Google Scholar). in toxin A caused a in the histological injury score SbS against this histological injury toxin A, toxin A < we found that SbS inhibited toxin A induced chemokine secretion in human we levels of the chemokine the mouse of in mouse ileal in toxin A increased KC in the ileal by of the ileal SbS toxin KC SbS not KC toxin A, toxin A < difficile is a a variety of gastrointestinal including antibiotic-associated diarrhea and colitis (4Kelly C.P. Pothoulakis C. LaMont N. Engl. J. Med. PubMed Scopus Google Scholar). S. boulardii used and in of to against intestinal and secretion caused by a wide variety of enteric including C. difficile L.V. J. Med. PubMed Google J. PubMed Scopus Google Scholar). In a S. boulardii was also in in M. M. PubMed Scopus Google and the protective and effects of probiotic S. boulardii in enteric infections and in inflammatory in humans not beneficial effects of S. boulardii to hypothesize that this probiotic yeast of host signaling pathways that intestinal and that S. boulardii its in by host MAP signaling in and in that S. boulardii inhibited production induced by IL-1β or toxin A in a dose-dependent that the effect of SbS is and not of or protein production S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). is that MAP production in to or S. M. PubMed Scopus Google J. Google Scholar) C. difficile toxin A M. S. S. Pothoulakis C. LaMont C.P. J. PubMed Scopus Google Scholar). that the activation of Erk1/2 and JNK/SAPK by IL-1β and toxin A inhibited by the of SbS in human and SbS also significantly inhibits Erk1/2 activation in toxin mouse ileal A effect is JNK/SAPK activation but is significant to toxin A SbS not the activation of p38 in NCM460 cells by IL-1β or toxin A and p38 activation in the in mouse ileal loop used of ileal the that we the of not intestinal cells. the of SbS inhibition of activation on MAP in its effect in NCM460 cells in inhibition of Erk1/2 activation and no significant effect on p38 MAP that or J. PubMed Scopus Google J. PubMed Scopus Google S. J.L. PubMed Scopus Google Scholar), this that the of SbS is involved Erk1/2 and JNK/SAPK and or not we that Sb also inhibited or production human cells and cells S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). a by S. Infect. Immun. PubMed Scopus Google Scholar) that the of S. boulardii yeast to human and MAP activation study S. boulardii and of human cells to Chang Chang J. Google Scholar). the hypothesis that S. boulardii is of host signaling of C. difficile toxin A this S. Infect. Immun. PubMed Scopus Google Scholar), or S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). This effect on host signaling S. boulardii effects on a wide variety of gastrointestinal whereby S. boulardii host signaling is not to this probiotic to host signaling that intestinal is of S. and of and inhibits the activation of the in intestinal cells C. Chang PubMed Scopus Google Scholar). also that inhibits activation of the p38 MAP by or but no effect on the J. PubMed Scopus Google Scholar). the that beneficial effects of in enteric mediated of host or intestinal to the of the gastrointestinal PubMed Scopus Google Scholar). of the probiotic of the intestinal to the of effect of probiotic the of and inflammatory C. difficile is a a variety of gastrointestinal including antibiotic-associated diarrhea and colitis (4Kelly C.P. Pothoulakis C. LaMont N. Engl. J. Med. PubMed Scopus Google Scholar). S. boulardii used and in of to against intestinal and secretion caused by a wide variety of enteric including C. difficile L.V. J. Med. PubMed Google J. PubMed Scopus Google Scholar). In a S. boulardii was also in in M. M. PubMed Scopus Google Scholar). and the protective and effects of probiotic S. boulardii in enteric infections and in inflammatory in humans not beneficial effects of S. boulardii to hypothesize that this probiotic yeast of host signaling pathways that intestinal and that S. boulardii its in by host MAP signaling in and in that S. boulardii inhibited production induced by IL-1β or toxin A in a dose-dependent that the effect of SbS is and not of or protein production S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). is that MAP production in to or S. M. PubMed Scopus Google J. Google Scholar) C. difficile toxin A M. S. S. Pothoulakis C. LaMont C.P. J. PubMed Scopus Google Scholar). that the activation of Erk1/2 and JNK/SAPK by IL-1β and toxin A inhibited by the of SbS in human and SbS also significantly inhibits Erk1/2 activation in toxin mouse ileal A effect is JNK/SAPK activation but is significant to toxin A SbS not the activation of p38 in NCM460 cells by IL-1β or toxin A and p38 activation in the in mouse ileal loop used of ileal the that we the of not intestinal cells. the of SbS inhibition of activation on MAP in its effect in NCM460 cells in inhibition of Erk1/2 activation and no significant effect on p38 MAP that or J. PubMed Scopus Google J. PubMed Scopus Google S. J.L. PubMed Scopus Google Scholar), this that the of SbS is involved Erk1/2 and JNK/SAPK and or not we that Sb also inhibited or production human cells and cells S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). a by S. Infect. Immun. PubMed Scopus Google Scholar) that the of S. boulardii yeast to human and MAP activation study S. boulardii and of human cells to Chang Chang J. Google Scholar). the hypothesis that S. boulardii is of host signaling of C. difficile toxin A this S. Infect. Immun. PubMed Scopus Google Scholar), or S. S. S. Pothoulakis C. C.P. PubMed Scopus Google Scholar). This effect on host signaling S. boulardii effects on a wide variety of gastrointestinal whereby S. boulardii host signaling is not to this probiotic to host signaling that intestinal is of S. and of and inhibits the activation of the in intestinal cells C. Chang PubMed Scopus Google Scholar). also that inhibits activation of the p38 MAP by or but no effect on the J. PubMed Scopus Google Scholar). the that beneficial effects of in enteric mediated of host or intestinal to the of the gastrointestinal PubMed Scopus Google Scholar). of the probiotic of the intestinal to the of effect of probiotic the of and inflammatory