Saccharomyces boulardii monograph

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Background

Saccharomyces boulardii (SB) is a beneficial probiotic, non-colonising yeast. It modulates the host’s innate gastrointestinal (GIT) immune response and improves GIT integrity.

It was discovered in 1920, when French microbiologist Henri Boulard visited IndoChina in search of new yeast strains for use in the fermenting process. Coincidently the local population was in the midst of a cholera outbreak, and Boulard noted consumption of a tea to prevent the severe diarrhoea disease. The tea was prepared by cooking down the skins of mangosteen and lychee fruits and on closer investigation Boulard isolated a special strain of yeast, now named Saccharomyces boulardii.[1]

Numerous trials have since demonstrated SB’s safety and efficacy in both children and adults, and these positive results see continued research on its benefits for gastrointestinal disease prevention and treatment.

SB is classified as a subspecies of Saccharomyces cerevisiae (brewer’s yeast), exhibiting the same genotype, but significant differences in metabolism and physiological characteristics to other S. cerevisiae strains.[1] SB’s identified antipathogen effects also set it apart from other members of the brewer’s yeast family. 

SB is resistant to the low pH of gastric acid and tolerant to bile acids. It grows at an unusually high temperature of 37°C, whereas other S. cerevisiae strains prefer cooler temperatures (30-33°C) and do not survive well in acid pH ranges.[1] This stability makes it a commercially viable probiotic, stable in storage without refrigeration.

As a yeast, non-bacterial probiotic, SB’s effectiveness is maintained when administered concurrently with antibiotics. When consumed, SB rapidly establishes itself in the GIT and multiplies in high numbers.[2,3] With daily administration it is found throughout the entire digestive system, yet will be undetectable within two to five days after cessation of therapy.[2,4]

SB exhibits extensive health-promoting actions both locally, within the GIT and systemically. For decades SB has been used to protect against intestinal injury and inflammation, for the prevention of antibiotic-associated diarrhoea (AAD) and traveller’s diarrhoea, reduction of Helicobacter pylori treatment-related symptoms, prevention of Clostridium difficile disease recurrences, irritable bowel syndrome (IBS), Crohn’s disease and giardiasis. The use of SB as a therapeutic probiotic is evidence-based for both efficacy and safety for several types of diarrhoea.[1,5-9]

Of 31 randomised, placebo-controlled treatment arms in 27 peer reviewed trials from the published medical literature between 1976 and 2009, SB was found to be significantly efficacious and safe in 84% of those treatment arms.[1]

Key benefits

  • Improves sIgA release
  • Antipathogenic and antitoxin
  • Anti-inflammatory
    • Inhibits NFkB, TNF-alpha, IL-6, IL-8, and VEGFR signalling
  • Trophic effects
    • Restores function to GIT mucosa
    • Restores fluid transport pathways (reducing diarrhoea)
  • Improves disaccharide and brush border enzyme release 
  • Supportive to intestinal integrity
    • Suppresses undesirable LPS passage
  • Protects gastric and intestinal mucosa
  • During antibiotic therapy, supports barrier function until microflora is re-established

Clinical applications

  • Inflammatory bowel disease (IBD)
  • Irritable bowel syndrome (IBS)
  • Antibiotic-associated diarrhoea (AAD)
  • Infectious diarrhoea 
    • Acute diarrhoea
    • Clostridium difficile
    • Cholera
    • Giardiasis
    • Escherichia coli
    • Traveller’s diarrhoea
  • Digestive concerns and mild food intolerances 
  • Compromised mucosal immunity
  • Other GIT-related infections
    • Helicobacter pylori and peptic ulcer (supportive triple therapy)
    • Candidiasis
    • Salmonella typhimurium
  • Systemic inflammation stemming from LPS passage
  • Intestinal hyperpermeability (leaky gut)

Mechanisms of action

Potential mechanisms of action of Saccharomyces boulardii in the intestinal lumen

The top row depicts the effects of various microbes.  The bottom row illustrates positive effects of SB.  

Antitoxinic: (1) Degrades toxins of pathogens.

Antimicrobial: (2) Inhibits bacterial growth and adherence, preserves tight junctions; (3) Produces SCFAs which nourish normal microbiota.

Trophic activity: (4) Releases polyamines which aid maturation of enterocytes; (5) Increases disaccharidase levels; (6) Increases presence of sIGA in lumen.

Anti-inflammatory: (7) Reduces inflammation.

Modulates inflammatory mediators

SB decreases the expression of nuclear factor-kappa beta (NFkB), tumour necrosis factor alpha (TNF-alpha), interleukin (IL) -6 and IL-8: all mediators of the body’s inflammatory response.[10,11] Moreso, it increases the expression of anti-inflammatory IL-10.[10] These immunomodulatory benefits appear to be attributable to not only the whole yeast, but also by secreted factors able to interfere with signalling molecules controlling inflammation at different levels.[12]

In vitro and in vivo studies demonstrate a novel mechanism by which SB inhibits vascular endothelial growth factor receptor (VEGFR) signalling, an important mediator of IBD (promoting intestinal angiogenesis and inflammation).[13] Trials have shown SB to improve treatment outcomes in Crohn’s sufferers when taken concurrently with pharmaceutical anti-inflammatory therapy (mesalamine).[5]

Lipopolysaccharide (LPS) from pathogenic gram-negative bacteria (e.g. E. coli) are a known culprit in many systemic and GIT-related inflammatory conditions. LPS induce pro-inflammatory responses in the intestines, and at other organs when allowed passage through a compromised intestinal barrier. 

SB assists intestinal integrity through short-chain fatty acid (SCFA) synthesis and protection from intestinal injury, plus it is able to dephosphorylate LPS, inhibiting its negative effects.[12,14]

Increases gut immunity and integrity

SB increases SCFA, acetate, butyrate and propionate; an energy source for intestinal cells that exert a nutritive effect to the intestinal epithelium. The level of SCFAs in the bowel is related to the production and balance of intestinal microflora and they are also involved in water and electrolyte absorption.[15]

SB also encourages friendly probiotic bacteria to adhere to and colonise the GIT, supporting micro-ecology. The combination of these actions inhibits proliferation of unhealthy micro-organisms, while supporting the health of the intestinal environment and strengthening the structure of the epithelial cells in the gut mucosa.[15-17]

SB increases secretory IgA (sIgA) release, the predominant immunoglobulin found in the mucosal secretions of the body.[18] As the key agent in mucosal immunity, sIgA neutralises toxins, agglutinates micro-organisms and prevents the adherence of pathogens (e.g. bacteria, viruses and protozoa) to the mucosal epithelial cells.[19] It screens food proteins from T-cell mediated inflammatory responses, thus down-regulating food allergies.[20

Low levels of sIgA are therefore associated with intestinal candidiasis, digestive disturbances and increased inflammatory response.

Activates disaccharide enzymes – healthy carbohydrate metabolism

Disaccharidases are enzymes that reside on the microvilli (brush border) in the intestinal tract, breaking disaccharides into monosaccharide molecules. SB increases the activity of the disaccharide (carbohydrate) enzymes: sucrase, maltase and lactase. This improves the body’s natural metabolism of carbohydrates, ameliorating food sensitivities and digestive discomfort. Improved carbohydrate metabolism leads to an increase in the available fuel for energy production and minimises residual substrates that ferment.[21]

Antibiotic-associated diarrhoea (AAD)

When normal intestinal barrier protection and microbial balance is disrupted, an individual is susceptible to complications including diarrhoea.

Antibiotics may compromise the beneficial commensal colonies within the GIT, and allow pathogen proliferation. Furthermore, specific antibiotics may contribute to diarrhoea via functional disturbances in intestinal carbohydrate or bile acid metabolism, allergic and toxic effects on the intestinal mucosa, and/or effects on motility.[22]

Meta-analyses confirm SB’s benefit on AAD prevention and the reduction of severity and duration of diarrhoea in children[23] and adults.[1] This beneficial function is attributed to its antipathogenic and trophic effects within the GIT.

The microbiota can take six to eight weeks to recover after antibiotic cessation, and SB may act as a surrogate to normal microflora until recovery is achieved. SB therapy may be recommended to continue for at least six weeks post antibiotic therapy as delayed-onset AAD has been noted.[1]

Traveller’s diarrhoea

Many of the above pathogens are known culprits in the pathogenesis of traveller’s diarrhoea.

SB displays comprehensive benefits in the treatment and prevention of pathogen-associated diarrhoea. The yeast works to prevent pathogenic adherence and proliferation, plus exhibits trophic effects on local cells (e.g. restoring fluid transport pathways).[1]

Furthermore, many pathogens exert their negative effects on health via the release of one or more toxins, and SB’s benefit lies also in its unique anti-toxin functions. The probiotic produces enzymes that function to directly destroy and/or neutralise such toxins, limiting symptoms.[24]

Helicobacter pylori and peptic ulcer

A meta-analysis reviewed the use of SB in conjunction with standard triple therapy for H. pylori and supported the concurrent use of SB for improving eradication rates and decreasing overall therapy-related side effects (improved treatment tolerability, reducing AAD, epigastric discomfort and post-treatment dyspepsia symptoms independent of H. pylori status).[7,25]

Interestingly, preliminary animal trials suggest SB may provide some benefit in the prevention and treatment of ulcers induced by non-steroidal anti-inflammatory drugs (e.g. ibuprofen).[26]

Clostridium difficile

C. difficile is a major cause of antibiotic-associated diarrhoea, particularly within the hospital setting.[8] Toxins A and B released by the pathogen are responsible for the pathogenesis of the disease. In this case 54kDa serine protease is the useful enzyme produced by SB. It directly degrades toxin A and B and destroys the colonic receptor site for C. difficile, preventing its adherence.[24]

SB is useful in conjunction with antibiotic therapy for C. difficile, showing benefit in preventing recurrence of the infection.[1,12

E.coli and cholera

In addition to 54kDa serine protease, investigations into SB’s antitoxin effects have identified beneficial enzymes including 63kDa phosphatase (destroys the endotoxin of E. coli)[14] and 120kDa protein (reduces the effects of a cholera toxin).[27]

Blastocystis hominis

SB was found to be comparable to metronidazole (antibiotic) use in children with symptomatic B. hominis infection. In the study, both SB and the antibiotic were found effective in addressing symptoms (clinical cure rate of 94.4% in SB group A versus 73.3% in metronidazole group B), and parasite presence (parasitological cure rate 94.4% in group A versus 93.3% in group B).[28]

Irritable bowel syndrome (IBS)

A meta-analysis of 20 trials with 23 probiotic treatment arms and a total of 1404 subjects of the use of SB in IBS found the yeast was associated with improvement in global IBS symptoms compared to placebo and reduced symptoms including abdominal pain, bloating and diarrhoea.[29]

Clinical studies

Acute childhood diarrhoea

Background: To test for the efficacy and safety of SB in acute childhood diarrhoea.

Subjects/Method: Children aged between three months and five years with acute onset diarrhoea (of less than 48 hours).

Intervention: Randomly given either a placebo or 250mg Saccharomyces boulardii twice daily for five days.

Results: The mean post intervention duration of diarrhoea was significantly shorter in SB group compared to placebo group (52 hours compared to 64 hours). The time of appearance of first semi formed stool in SB group was significantly shorter than the placebo group (39 hours compared to 54 hours).

Riaz M, Alam S, Malik A, et al. Efficacy and safety of Saccharomyces boulardii in acute childhood diarrhea: a double blind randomised controlled trial. Indian J Pedatr 2012;79(4):478-482.

Crohn’s disease

Background: Crohn’s disease (CD) is characterised by a reduction in mucosal integrity that permits antigen penetration into the intestinal tissue. The administration of probiotics has been suggested to improve the barrier function of the mucosa. The objective of this study was to evaluate the influence of SB on the intestinal permeability in CD.

Subjects/Method: Thirty-four patients with CD, baseline medications (mesalamine, azathioprine, prednisone, metronidazole and/or thalidomide) were maintained.  

Intervention: Randomised for treatment with either placebo or 200mg SB. Intestinal permeability (lactulose/mannitol ratio) was evaluated immediately before the beginning of treatment and at the end of the first and third treatment month.

Results: In the placebo group, there was an increase in lactulose/mannitol ratio by 0.004 at the end of the third month. In the SB group, there was an improvement in intestinal permeability with a decrease in the lactulose/mannitol ratio by 0.008 in the same period. Patients with CD in remission present alterations in the integrity of the intestinal mucosal barrier according to lactulose/mannitol ratio. SB added to baseline therapy improved intestinal permeability in these patients, even though complete normalisation was not achieved.

Vilela E, Ferrari M, Torres H, et al. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn’s disease in remission. Scand J Gastroenterol 2008;43(7):842-848.

Giardia lamblia infection

Background: 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 micro-organisms for preventing or treating gastrointestinal diseases, but little is known about their efficacy against protozoal infections. The principal objective of this study was to evaluate the efficacy of SB against G. lamblia infections.

Subjects/Method: A 10-day double-blind, placebo-controlled study on 65 adult patients with giardiasis.

Intervention: Group 1 (30 patients) included metronidazole 750mg three times daily with 250mg SB twice daily; group 2 (35 patients) was treated with metronidazole 750mg three times daily and placebo. Patients were re-examined at two and four weeks after treatment, and stool examinations were performed.

Results: At week two, G. lamblia cysts were detected in six cases of group 2 (17.1%) and none in group 1. At the end of the fourth week, presence of the cysts continued in the same six cases in group 2. These findings indicated that SB may be effective in treating giardiasis when combined with metronidazole therapy.

Besirbellioglu BA, Ulcay A, Can M, et al. Saccharomyces boulardii and infection due to Giardia lamblia. Scand J Infect Dis 2006;38(6-7):479-481.

Dosage range for treatments according to clinical studies

Cautions and contraindications

  • SB has not been shown to be contraindicated during pregnancy or lactation.
  • SB is not a common allergen; only those with a true yeast allergy should avoid.[16]
  • SB has been clinically trialled in infants and children without any serious side effects reported.[32]
  • Patients with long-term dysbiosis may need to start at a lower dose. 
  • Caution should be taken when prescribing SB to immunocompromised individuals on intravenous lines.[16]
  • Caution is required in case of perforated bowel or recent bowel surgery. 
  • Antifungal medications, nutritionals or herbals may affect the activity of SB. Take SB two hours before or four to six hours after taking antifungals.

References

  1. McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol 2010;16(18):2202-2222. [Full text]
     
  2. D’Souza AL, Rajkumar C, Cooke J, et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324:1361. [Full text]
     
  3. McCullough MJ, Clemons KV, McCusker JH, et al. Species identification and virulence attributes of Saccharomyces boulardii (nom. inval.). J Clin Microbiology 1998;36(9):2613-2617. [Full text]
     
  4. McFarland LV, Bernasconi P. Saccharomyces boulardii. A review of an innovative biotherapeutic agent. Microbial Ecology in Health and Disease 1993;6:157-171. [Abstract]
     
  5. Guslandi M, Mezzi G, Sorghi M, et al. Saccharomyces boulardii in maintenance treatment of Crohn’s disease. Dig Dis Sci 2000;45(7):1462-1464. [Abstract]
     
  6. O’Connor A, Gisbert JP, McNamara D, et al. Treatment of Helicobacter pylori infection 2011. Helicobacter 2011;16 Suppl 1:53-58. [Abstract]
     
  7. Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther 2010;32(9):1069-1079. [Full text]
     
  8. Tung JM, Dolovich LR, Lee CH. Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systematic review. Can J Gastroenterol 2009;23(12):817-821. [Full text]
     
  9. Besirbellioglu BA, Ulcay A, Can M, et al. Saccharomyces boulardii and infection due to Giardia lamblia. Scand J Infect Dis 2006;38(6-7):479-481. [Abstract]
     
  10. Kelesidis T, Pothoulakis C. Efficacy and safety of the probiotic Saccharomyces boulardii for the prevention and therapy of gastrointestinal disorders. Therap Adv Gastroenterol 2012;5(2):111-125. [Full text]
     
  11. Fitzpatrick LR. Probiotics for the treatment of Clostridium difficile associated disease. World J Gastrointest Pathophysiol 2013;4(3):47-52. [Full text]
     
  12. Pothoulakis C. Review article: anti-inflammatory mechanisms of action of Saccharomyces boulardii. Aliment Pharmacol Ther 2009;30(8):826-833. [Full text]
     
  13. Chen X, Yang G, Song J, et al. Probiotic yeast inhibits VEGFR signaling and angiogeneis in intestinal inflammation. PLoS ONE 2013;8(5):e64227. [Full text]
     
  14. Buts JP, Dekeyser N, Stilmant C, et al. Saccharomyces boulardii produces in rat small intestine a novel protein phosphatase that inhibits Escherichia coli endotoxin by dephosphorylation. Pediatr Res 2006;60(1):24-29. [Abstract]
     
  15. Girard-Pipau F. Intestinal microflora, short chain and cellular fatty acids, influence of a probiotic Saccharomyces boulardii. Microbial Ecology in Health and Disease 2002;14(4):220-227. [Abstract]
     
  16. Vandenplas Y. Bacteria and yeasts in the treatment of acute and chronic infectious diarrhoea. Part II: yeasts. Clin Microbiol Infect 1999;5:389-395. [Full text]
     
  17. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870-876. [Abstract]
     
  18. Underdown B, Schiff M. Immunoglobulin A: strategic defense initiative at the mucosal surface. Annu Rev Immunol 1986;4:389-417. [Abstract]
     
  19. Mantis NJ, Rol N, Corthesy B. Secretary IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunology 2011;4:603-611. [Full text]
     
  20. Stokes CR, Soothill JF, Turner MW. Immune exclusion is a function of IgA. Nature 1975;255:745-746. [Abstract]
     
  21. Brody T. Nutritional biochemistry, 2nd ed. San Diego: Academic Press, 1999.
     
  22. Högenauer C, Hammer HF, Krejs GJ, et al. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis 1998;27(4):702-710. [Full text]
     
  23. Johnston BC, Supina AL, Ospina M, et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev 2011;(11):CD004827. [Abstract]
     
  24. Castagliuolo I, LaMont JT, Nikulasson ST, et al. Saccharomyces boulardii protease inhibits Clostridium difficile toxin A effects in the rat ileum. Infect Immun 1996;64(12):5225-5232. [Full text]
     
  25. Cindoruk M, Erkan G, Karakan T, et al. Efficacy and safety of Saccharomyces boulardii in the 14-day triple anti-Helicobacter pylori therapy: a prospective randomized placebo-controlled double-blind study. Helicobacter 2007;12(4):309-316. [Abstract]
     
  26. Girard P, Coppé MC, Pansart Y, et al. Gastroprotective effect of Saccharomyces boulardii in a rat model of ibuprofen-induced gastric ulcer. Pharmacology 2010;85(3):188-193. [Abstract]
     
  27. Czerucka D, Rampal P. Effect of Saccharomyces boulardii on cAMP- and Ca2+ -dependent Cl- secretion in T84 cells. Dig Dis Sci 1999;44(11):2359-2368. [Abstract]
     
  28. Dinleyici EC, Eren M, Dogan N, et al. Clinical efficacy of Saccharomyces boulardii or metronidazole in symptomatic children with Blastocystis hominis infection. Parasitol Res 2011;108(3):541-545. [Abstract]
     
  29. McFarland LV, Dublin S. Meta-analysis of probiotics for the treatment of irritable bowel syndrome. World J Gastroenterol 2008;14(17):2650-2661. [Full text]
     
  30. Vilela E, Ferrari M, Torres H, et al. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn’s disease in remission. Scand J Gastroenterol 2008;43(7):842-848. [Abstract]
     
  31. Ducluzeau R, Bensaada M. Comparative effect of a single or continuous administration of Saccharomyces boulardii on the establishment of various strains of candida in the digestive tract of gnotobiotic mice. Ann Microbiol 1982;1338:491-501. [Abstract]
     
  32. Guillot CC, Bacallao EG, Dominguez MS, et al. Effects of Saccharomyces boulardii in children with chronic diarrhea, especially cases due to giardiasis. Rev Mex Pueric Pediatr 1995;2(12):1-11. 

 

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