Research & Case History Support

A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease.

MacFarland LV, et al

Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.

OBJECTIVE--To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile-associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole). DESIGN--A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. SETTING--National referral study of ambulatory or hospitalized patients from three main study coordinating centers. PATIENTS--A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. INTERVENTION--Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. MAIN OUTCOME MEASURE--Recurrence of active CDD. RESULTS--A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P = .04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P = .86). There were no serious adverse reactions associated with S boulardii. CONCLUSIONS--The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD.

PMID: 8201735

Cochrane Database Syst Review 2007 Apr 18;(2):CD004827.

Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

Johnston B, et al

BACKGROUND: Antibiotics alter the microbial balance within the gastrointestinal tract. Probiotics may prevent antibiotic-associated diarrhea (AAD) via restoration of the gut microflora. Antibiotics are prescribed frequently in children and AAD is common in this population. OBJECTIVES: To assess the efficacy and adverse effects of probiotics (any specified strain or dose) for the prevention of antibiotic-associated diarrhea in children.To assess adverse events associated with the use of probiotics when co-administered with antibiotics in children. SEARCH STRATEGY: MEDLINE, EMBASE, CENTRAL, CINAHL , AMED, and the Web of Science (inception to August 2006) were searched along with specialized registers including the Cochrane IBD/FBD Review Group, CISCOM, Chalmers PedCAM Research Register and trial registries from inception to 2005. Letters were sent to authors of included trials, nutra/pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were hand searched. SELECTION CRITERIA: Randomized, parallel, controlled (placebo, active, or no treatment) trials comparing co-administered probiotics with antibiotics for the prevention of diarrhea secondary to antibiotic use in children (0 to 18 years). DATA COLLECTION AND ANALYSIS: Methodological quality assessment and data extraction were conducted independently by two authors (BCJ, AS). Dichotomous data (incidence of diarrhea, adverse events) were combined using pooled relative risks, and continuous data (mean duration of diarrhea, mean daily stool frequency) as weighted mean differences, along with their corresponding 95% confidence intervals. Adverse events were summarized using risk difference. For overall pooled results on the incidence of diarrhea, a priori sensitivity analyses included per protocol versus intention to treat, random versus fixed effects, and methodological quality criterion. Subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, and antibiotic agent. MAIN RESULTS: Ten studies met the inclusion criteria. Trials included treatment with either Lactobacilli spp., Bifidobacterium spp., Streptococcus spp., or Saccharomyces boulardii alone or in combination. Six studies used a single strain probiotic agent and four combined two probiotic strains.The per protocol analysis for 9/10 trials reporting on the incidence of diarrhea show statistically significant results favouring probiotics over active/non active controls (RR 0.49; 95% CI 0.32 to 0.74). However, intention to treat analysis showed non-significant results overall (RR 0.90; 95% CI 0.50 to 1.63). Five of ten trials monitored for adverse events (n = 647); none reported a serious adverse event. AUTHORS' CONCLUSIONS: Probiotics show promise for the prevention of pediatric AAD. While per protocol analysis yields treatment effect estimates that are both statistically and clinically significant, as does analysis of high quality studies, the estimate from the intention to treat analysis was not statistically significant. Future studies should involve probiotic strains and doses with the most promising evidence (e.g., Lactobacillus GG, Lactobacillus sporogenes, Saccharomyces boulardii at 5 to 40 billion colony forming units/day). Research done to date does not permit determination of the effect of age (e.g., infant versus older children) or antibiotic duration (e.g., 5 days versus 10 days). Future trials would benefit from a validated primary outcome measure for antibiotic-associated diarrhea that is sensitive to change and reflects what treatment effect clinicians, parents, and children consider important. The current data are promising, but it is premature to routinely recommend probiotics for the prevention of pediatric AAD.

PMID: 17443557 [PubMed - in process]

ACta Paediatr 2007 Apr;96(4):538-41. Epub 2007 Feb 14.

Saccharomyces boulardii in acute childhood diarrhoea: a randomized, placebo-controlled study.

Villarruel G, et al

Hospital Privado Materno Infantil, National University of Salta, Campo Castañs, Salta, Argentina.

OBJECTIVE: To evaluate the efficacy of the probiotic yeast Saccharomyces boulardii (S. boulardii) as an adjuvant to oral rehydration solution (ORS) in shortening the duration of acute infectious gastroenteritis in children less than 2 years old in ambulatory care. MATERIALS AND METHODS: In a period of 1 year, 100 outpatients between 3 and 24 months old presenting with acute mild to moderate diarrhoea of less than 7 days duration, were included in a double-blind, randomized, placebo-controlled trial evaluating the efficacy of S. boulardii administered for 6 days. Twelve children were lost in follow-up; the data of 88 children could be analysed (44 in the placebo and 44 in the S. boulardii group). Seventy-two patients were followed for one month (37 in the placebo and 35 in the S. boulardii group) allowing the calculation of the duration of diarrhoea. RESULTS: The mean duration of diarrhoea was 6.16 days (range 2-13 days) in the placebo group and 4.70 days (range 2-10 days) in the S. boulardii group (p<0.05). On the 4th day, the patients in the S. boulardii group passed 2.5+/-1.4 stools/day versus 3.5+/-1.8 in the placebo group (p<0.001). The risk of having diarrhoea lasting more than 7 days was lower in the S. boulardii group (3/44 versus 12/44; RR 0.25; 95% CI 0.1-0.8). In no patient diarrhoea persisted longer than 14 days. A statistically significant difference was observed in the number of stools on the 4th and 7th day favouring the subgroup that received early treatment (within the first 48 h of the onset of diarrhoea). The administration of antibiotics before inclusion did not make any difference. CONCLUSION: S. boulardii as an adjuvant to ORS in ambulatory care in children less than 2 years old with mild or moderate acute diarrhoea decreased the duration of diarrhoea, accelerated recovery and reduced the risk of prolonged diarrhoea. The data also indicate increased efficacy if S. boulardii is administered within the first 48 h of the onset of diarrhoea.

PMID: 17306006

Eur J Clin Nutr. 2007 Feb 28; [Epub ahead of print]

Effect of dietary intervention with different pre- and probiotics on intestinal bacterial enzyme activities.

De Preter V, et al

1Department of Gastrointestinal Research, University Hospital Gasthuisberg, Leuven, Belgium.

Objective:To investigate the influence of different pre- and probiotics on faecal beta-glucuronidase and beta-glucosidase activity, as one of the claimed beneficial effects of pre- and probiotics is the hypothesis that these substrates are able to reduce the production of toxic and carcinogenic metabolites by suppressing specific enzyme activities in the colon.Setting:Department of Gastrointestinal Research, University Hospital Gasthuisberg, KU Leuven, Belgium.Design and subjects:The effect was evaluated in a randomized, crossover study in 53 healthy volunteers who were randomly assigned to one of five treatment groups.Interventions:At the start and after a 4-week treatment period, the healthy volunteers collected faeces during 72 h. Lactulose and oligofructose-enriched inulin (OF-IN) were chosen as prebiotics, whereas Lactobacillus casei Shirota, Bifidobacterium breve and Saccharomyces boulardii were selected as probiotics. Two synbiotic combinations were evaluated as well. The enzyme activity was assessed spectrophotometricly.Results:Lactulose and OF-IN significantly decreased beta-glucuronidase activity, whereas a tendency to a decreased beta-glucuronidase activity was observed after L. casei Shirota and B. breve intake. To the contrary, B. breve increased beta-glucosidase levels. Supplementation with the synbiotic did not appear to be more beneficial than either compound alone. No influence of S. boulardii was noted.Conclusions:Administration of lactulose, OF-IN, L. casei Shirota or B. breve resulted in a decrease of the beta-glucuronidase activity, which is considered beneficial for the host.European Journal of Clinical Nutrition advance online publication, 28 February 2007; doi:10.1038/sj.ejcn.1602706.

PMID: 17327863

Gastroenterology 2006 Dec;131(6):1812-25.

Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes.

Dammasso G, et al

Laboratoire de Gastroentélogie, Facultée Mécine, IFR50, UNSA, Nice, France.

BACKGROUND & AIMS: Saccharomyces boulardii is a nonpathogenic yeast used for treatment of diarrhea. We used a mice model of inflammatory bowel disease (IBD) to analyze the effects of S boulardii on inflammation. METHODS: Lymphocyte-transferred SCID mice, displaying IBD, were fed daily with S boulardii. Weight loss and inflammatory status of the colon were monitored. Nuclear factor-kappaB activity was assessed in the colon. The CD4(+) T-cell production of interferon (IFN) gamma was evaluated by enzyme-linked immunosorbent assay, and a comprehensive reverse-transcription polymerase chain reaction (RT-PCR) analysis for both colon and mesenteric lymph nodes was performed. Finally, we analyzed cell migration mechanisms in vitro and in vivo. RESULTS: S boulardii treatment inhibits IBD. S boulardii induces an accumulation of IFN-gamma-producing T-helper 1 cells within the mesenteric lymph nodes correlated with a diminution of CD4(+) T-cell number and IFN-gamma production by CD4+ T cells within the colon. The influence of S boulardii treatment on cell accumulation in mesenteric lymph nodes was also observed in normal BALB/c mice and involves modifications of lymph node endothelial cell adhesiveness by a yeast secretion product. CONCLUSIONS: S boulardii has a unique action on inflammation by a specific alteration of the migratory behavior of T cells, which accumulate in mesenteric lymph nodes. Therefore, S boulardii treatment limits the infiltration of T-helper 1 cells in the inflammed colon and the amplification of inflammation induced by proinflammatory cytokines production. These results suggest that S boulardii administration may have a beneficial effect in the treatment of IBD.

PMID: 17087945

Pediatric Nephrology 2006 Jun;21(6):807-10. Epub 2006 Apr 20.

Influence of oral intake of Saccharomyces boulardii on Escherichia coli in enteric flora.

Akil I, et al

Department of Pediatric Nephrology, Celal Bayar University, Manisa, Turkey. ipek.akil@bayar.edu.tr

Enteric flora constitutes 95% of the cells in the human body. It has been shown that the bacterial content of this flora is affected by diet and changes in nutrition. Considering that urinary tract infections (UTI) are mostly due to ascending infections from the gut flora, the importance of the elements of this flora and their characteristics becomes more evident. The aim of this study was to evaluate the influence of oral Saccharomyces boulardii (S. boulardii) intake on the number of Escherichia coli (E. coli) colonies in the colon. This study was carried out with 14 boys and 10 girls (total of 24 children) aged between 36 and 192 months (mean: 104.3+/-45.1 months). A commercial capsule or powder containing 5 billion colony-forming units (cfu) of S. boulardii was administered once a day for 5 days. The number of E. coli and yeast colonies was measured in the stool samples of the study group before and after the use of this drug. Before treatment, the mean number of E. coli colonies in g/ml stool was 384,625+/-445,744. This number decreased significantly to 6,283+/-20,283 after treatment (p=0.00). S. boulardii was not detected in stool before treatment and the number of colonies increased to 11,047+/-26,754 in g/ml stool. S. boulardii may be effective in reducing the number of E. coli colonies in stool. The influence of this finding on clinical practice such as prevention of UTI needs to be clarified by further studies.

Biochem Biophys Res Comm 2006 Apr 28;343(1):69-76. Epub 2006 Feb 23.

Saccharomyces boulardii produces a soluble anti-inflammatory factor that inhibits NF-kappaB-mediated IL-8 gene expression.

Sougioultzis S, et al

Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Saccharomyces boulardii (Sb) is a non-pathogenic yeast that ameliorates intestinal injury and inflammation caused by a wide variety of enteric pathogens. We hypothesized that Sb may exert its probiotic effects by modulation of host cell signaling and pro-inflammatory gene expression. Human HT-29 colonocytes and THP-1 monocytes were stimulated with IL-1beta, TNFalpha or LPS in the presence or absence of Sb culture supernatant (SbS). IL-8 protein and mRNA levels were measured by ELISA and RT-PCR, respectively. The effect of SbS on IkappaB alpha degradation was studied by Western blotting and on NF-kappaB-DNA binding by EMSA. NF-kappaB-regulated gene expression was evaluated by transient transfection of THP-1 cells with a NF-kappaB-responsive luciferase reporter gene. SbS inhibited IL-8 protein production in IL-1beta or TNFalpha stimulated HT-29 cells (by 75% and 85%, respectively; P<0.001) and prevented IL-1beta-induced up-regulation of IL-8 mRNA. SbS also inhibited IL-8 production, prevented IkappaB alpha degradation, and reduced both NF-kappaB-DNA binding and NF-kappaB reporter gene up-regulation in IL-1beta or LPS-stimulated THP-1 cells. Purification and characterization studies indicate that the S. boulardii anti-inflammatory factor (SAIF) is small (<1 kDa), heat stable, and water soluble. The probiotic yeast Saccharomyces boulardii exerts an anti-inflammatory effect by producing a low molecular weight soluble factor that blocks NF-kappaB activation and NF-kappaB-mediated IL-8 gene expression in intestinal epithelial cells and monocytes. SAIF may mediate, at least in part, the beneficial effects of Saccharomyces boulardii in infectious and non-infectious human intestinal disease.

PMID: 16529714

Scand J Infectious Diseases 2006;38(6-7):479-81.

Saccharomyces boulardii and infection due to Giardia lamblia.

Besirbellioglu BA, et al

Gulhane Military Medical Academy, Department of Infectious Diseases and Clinical Microbiology, Ankara, Turkey.

Therapy with metronidazole is the recommended option in giardiasis. However, some clinical trial reports suggest the appearance of drug resistance to explain therapeutic failure. Several investigations have been carried out on the effect of probiotic microorganisms for preventing or treating gastrointestinal diseases, but little is known about their efficacy against protozoal infections. The principal objective of our study was to evaluate the efficacy of Saccharomyces boulardii against Giardia lamblia infections. A double-blind, placebo-controlled study was carried out on adult patients with giardiasis. Group 1 (30 patients) included metronidazole 750 mg 3 times daily along with S. boulardii capsules (250 mg b.i.d. orally) for 10 d while group 2 (35 patients) was treated with metronidazole 750 mg 3 times daily and with empty capsules as placebo for 10 d. Patients were re-examined at 2 and 4 weeks after treatment, and stool examinations were performed. At week 2, G. lamblia cysts were detected in 6 cases (17.1%) of group 2 and none in group 1. At the end of the fourth week, presence of the cysts continued in the same 6 cases in group 2 (control group). These findings indicated that S. boulardii may be effective in treating giardiasis when combined with metronidazole therapy.

PMID: 16798698

ACta Paediatr 2005 Dec;94(12):1747-51.

Effect of regular ingestion of Saccharomyces boulardii plus inulin or Lactobacillus acidophilus LB in children colonized by Helicobacter pylori.

Gotteland M, et al

Laboratory of Microbiology, University of Chile, Santiago, Chile. mgottela@inta.cl

AIM: To evaluate the effect of a probiotic, Lactobacillus acidophilus LB (LB), or a synbiotic, Saccharomyces boulardii plus inulin (SbI), on Helicobacter pylori (Hp) colonization in children. SUBJECTS AND METHODS: A clinical trial was carried out in a school from a low socio-economic area of Santiago. Two hundred and fifty-four asymptomatic children (8.40+/-1.62 y) were screened for Hp by the (13)C-Urea Breath Test ((13)C-UBT). Hp-positive children were randomly distributed into three groups to receive either antibiotic treatment (lanzoprazole, clarythromycin and amoxicillin) for 8 d, or SbI or LB daily for 8 wk. A second (13)C-UBT was carried out at this time. Spontaneous clearance was evaluated in the same way in 81 infected, untreated children. The differences in the delta(13)CO(2) over baseline values before and after treatments (?DOB) were evaluated. RESULTS: 182 subjects (71.7%) were colonized by Hp, and 141 of them completed their treatment (22.5% dropout). Hp was eradicated in 66%, 12% and 6.5% of the children from the Ab, SbI and LB groups, respectively, while no spontaneous clearance was observed in the children without treatment. A moderate but significant difference in ?DOB was detected in children receiving living SbI (-6.31; 95% CI: -11.84 to -0.79), but not in those receiving LB (+0.70; 95% CI: -5.84 to +7.24). CONCLUSION: S. boulardii seems promising as an agent that interferes with Hp in colonized individuals. More studies are needed to confirm these results and to elucidate the mechanisms by which Sb inhibits Hp.

PMID: 16421034