What is saccharomyces boulardii

Saccharomyces boulardii is a probiotic regulated as a dietary supplement intended for use by the general healthy population, not as a drug to prevent, treat, or mitigate disease. For dietary supplements, premarketing demonstration of safety and efficacy and approval by the Food and Drug Administration (FDA) are not required; only premarket notification is required. Probiotics are defined by the Food and Agriculture Organization (FAO) of the World Health Organization as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host ¹⁾, ²⁾. The term probiotic can be subcategorized to include probiotic drugs, probiotic foods (e.g., foods, food ingredients, and dietary supplements), direct-fed microbials (probiotics for animal use), and designer probiotics (genetically modified probiotics) ³⁾. In the United States, probiotic products are marketed to a generally healthy population as foods or dietary supplements ⁴⁾.

Saccharomyces boulardii CNCM I-745 is a fungus classified as a yeast, which routinely cannot be distinguished from Saccharomyces cerevisiae and at present is regarded as a subtype of Saccharomyces cerevisiae HANSEN CBS 5926 (a strain of baker’s yeast) ⁵⁾. These yeasts are widespread in nature and can be found on plants, fruit and in soil, being also used in the baking and brewing industry ⁶⁾. Usually, they are considered to be nonpathogenic commensals of the digestive tract, administered as probiotics for several indications, including Clostridium difficile-associated disease ⁷⁾. Saccharomyces boulardii CNCM I-745, the probiotic yeast is efficient for the treatment and prevention of diarrhea of various causes ⁸⁾. Saccharomyces boulardii CNCM I-745 has also been used in a variety of different clinical conditions, including human immunodeficiency virus (HIV) ⁹⁾ and Helicobacter pylori infection ¹⁰⁾.

Saccharomyces boulardii CNCM I-745 has an optimal growth temperature around 37°C and a relatively high acid tolerance ¹¹⁾, resulting in a good survival after gastric passage. A spectrum of favorable effects, including prebiotic effects ¹²⁾, toxin degradation effects ¹³⁾, pathogen binding effects ¹⁴⁾, anti-secretory effects ¹⁵⁾, physical barrier effects ¹⁶⁾, effects on the microbiota ¹⁷⁾, and on the immune system ¹⁸⁾ reduces the risk to develop diarrhea or counteract diarrhea.

Prebiotic effects are accomplished by cell wall components of Saccharomyces boulardii CNCM I-745, consisting of glucans, mannoproteins, and chitin which serve short-chain fatty acid producing bacteria as suitable substrates for fermentation ¹⁹⁾. Also, Saccharomyces boulardii CNCM I-745 restores intestinal barrier integrity by regulation of E-cadherin recycling ²⁰⁾. In several animal and human studies, a protective and stabilizing effect on the intestinal microbiota has been demonstrated, including the prevention of antibiotic-associated diarrhea by decreasing the antibiotic-induced reduction in the intestinal microbiota, as well as by supporting a faster regeneration of the intestinal microbiota following antibiotic therapy ²¹⁾.

Saccharomyces boulardii CNCM I-745 influences the infection-induced signalling cascades of its human host as well as the innate and adaptive immune system. In a healthy host, Saccharomyces boulardii CNCM I-745 leads to a general unspecific immune system activation ²²⁾, which can be considered advantageous in preventing diarrhea. During diarrhea, it attenuates an over-reacting inflammatory immune response and diarrheic leakage of fluids into the intestinal lumen ²³⁾. The combined effects by the yeast reduce colonization by pathogens and preservation of the integrity of the intestinal epithelial cell layer.

However, since the 1990s, an increasing number of publications of fungemia and invasive infections caused by Saccharomyces boulardii, particularly among intensive care unit (ICU) patients and individuals with multiple co-morbidities, have been reported in literature in patients treated with a probiotic preparation containing this yeast ²⁴⁾. Furthermore, it can also cause infections in otherwise healthy individuals ²⁵⁾.

Since recent increases in incidence and severity of Clostridium difficile infection, probiotics have been used to treat recurrent and/or refractory disease in hospitalized patients. Albeit rare, serious complications (i.e., fungemia) in other than healthy populations receiving probiotics have been reported in the literature. Specifically, most complications related to the administration of Saccharomyces boulardii have occurred in immunocompromised or critically ill patients or in those who had central venous catheters serving as a portal of entry of organisms from healthcare workers’ contaminated hands to patients’ bloodstream during administration ²⁶⁾. Careful risk assessment for patients and proper handling of the probiotic during administration need to be conducted before using probiotics as drugs in institutional settings. Vigilant reporting of adverse events resulting from probiotic use is necessary to establish the safety profile of these agents when they are used in other than healthy populations. Before use of a probiotic is considered for hospitalized patients, careful assessment of risk versus benefit must be made. To ensure patient safety, probiotics should be properly handled during administration ²⁷⁾. It has been postulated that further studies are needed to evaluate the efficacy of probiotic preparations, to determine the optimal dose and strain of probiotic, and possible adverse events related to their use in hospitalised patients ²⁸⁾.

Depending on the intended use of a probiotic, whether as a drug or a dietary supplement, regulatory requirements differ. According to the Food and Drug Administration (FDA) definition, a drug is an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease ²⁹⁾. If a probiotic is intended for use as a drug, then it must undergo the regulatory process as a drug, which is similar to that of any new therapeutic agent. An Investigational New Drug application must be submitted and authorized by FDA before an investigational or biological product can be administered to humans. The probiotic drug must be proven safe and effective for its intended use before marketing ³⁰⁾.

If a probiotic is intended for use as a dietary supplement, it is placed under the umbrella of “foods,” and as such is regulated by FDA’s Center for Food Safety and Applied Nutrition ³¹⁾. A dietary supplement is defined by the Dietary Supplement Health and Education Act of 1994 as a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. Supplements must contain >1 of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical (excluding tobacco); an amino acid; a dietary substance for use by persons to supplement the diet by increasing the total dietary intake; a concentrate, metabolite, constituent, extract; or combination of any of the above ³²⁾.

In contrast to drugs, dietary supplements do not need FDA approval before being marketed. However, manufacturers need to notify FDA before marketing a product. According to Dietary Supplement Health and Education Act of 1994, the manufacturer is responsible for determining that the dietary supplements that it manufactures or distributes are safe and that any representations or claims made about them are substantiated by adequate evidence to show that they are not false or misleading; the manufacturers need not provide FDA with evidence that substantiates the safety or purported benefits of their products, either before or after marketing. If a dietary supplement contains a new dietary ingredient that was not sold before October 15, 1994, then the manufacturer is required to notify FDA and demonstrate to FDA before marketing why the ingredient is reasonably expected to be safe for use in a dietary supplement. On June 22, 2007, FDA announced a final rule establishing Current Good Manufacturing Practice requirements for dietary supplements. To ensure the identity, purity, quality, strength, and composition of dietary supplements, those who manufacture, package, or hold dietary supplements must follow these regulations ³³⁾. Also, since implementation of the Dietary Supplement and Nonprescription Drug Consumer Protection Act in 2006, manufacturers and distributors of dietary supplements have been required to record and forward to FDA any directly received reports of serious adverse events associated with use of their products.

Be watchful with this combination

Medications for fungal infections (Antifungals): Saccharomyces boulardii is a fungus. Medications for fungal infections help reduce fungus in and on the body. Taking Saccharomyces boulardii with medications for fungal infections can reduce the effectiveness of Saccharomyces boulardii. Some medications for fungal infection include fluconazole (Diflucan), caspofungin (Cancidas), itraconazole (Sporanox) amphotericin (Ambisome), and others.

Saccharomyces boulardii benefits

Saccharomyces boulardii and diarrhea

Acute diarrhea

Two randomized controlled trials using Saccharomyces boulardii showed that this probiotic may be effective in treating acute adult diarrhea due to a variety of causes and can significantly lower diarrhea severity score compared with controls ³⁴⁾. Unfortunately, since the number of trials in this area is small and the causes were different in the two trials, only limited conclusions can be reached.

A recent randomized controlled trial conducted in 100 hospitalized children showed that Saccharomyces boulardii treatment for 5 days significantly reduces the mean duration of acute diarrhea and frequency of stools, and normalizes stool consistency ³⁵⁾. One randomized controlled trial regarding the efficacy of Saccharomyces boulardii for the prevention of acute diarrhea involved 100 children with acute watery diarrhea and reported a significant difference in the incidence of diarrheal episodes in the group receiving Saccharomyces boulardii compared with the control group during 2 months follow up ³⁶⁾.

A meta-analysis based on 5 randomized controlled trials (619 participants) ³⁷⁾ indicated that Saccharomyces boulardii significantly reduces the duration of acute childhood diarrhea and the risk of prolonged diarrhea compared with control ³⁸⁾. A meta-analysis of seven randomized controlled trials (944 participants) showed a reduction in the duration of acute childhood diarrhea by approximately 1 day in those treated with Saccharomyces boulardii compared with placebo ³⁹⁾. The absence of blinding as well as other factors such as ambulatory care may explain why Saccharomyces boulardii had no effect in a European randomized controlled trial ⁴⁰⁾. In summary, the findings from randomized controlled trials and guidelines from professional pediatric societies indicate that Saccharomyces boulardii may be an effective adjunct therapy in managing acute gastroenteritis in children ⁴¹⁾.

Persistent diarrhea

Results from two clinical trials indicate that Saccharomyces boulardii improves outcomes in children with persistent diarrhea ⁴²⁾. The relative significant reduction in persistent diarrhea in the Saccharomyces boulardii group compared with controls was approximately 50% ⁴³⁾. These results indicate that Saccharomyces boulardii is useful in the management of persistent diarrhea in children. However, studies with larger populations are needed to determine whether Saccharomyces boulardii therapy alone is also effective in children with persistent diarrhea.

Traveler’s diarrhea

A meta-analysis of 12 randomized controlled trials of various probiotics (including Saccharomyces boulardii) for the prevention of traveler’s diarrhea found a significant reduction in the risk of traveler’s diarrhea when probiotics are used ⁴⁴⁾. The relative significant reduction in traveler’s diarrhea in the Saccharomyces boulardii group compared with controls in two randomized controlled trials ranged between 5% and 11% ⁴⁵⁾. These limited numbers of studies indicate that probiotics may be more effective in preventing traveler’s diarrhea, rather than treating diarrhea once it becomes symptomatic.

Enteral nutrition-related diarrhea

Diarrhea is a significant problem in patients on total enteral nutrition (TEN) and may involve changes in intestinal short chain fatty acids (SCFAs) ⁴⁶⁾. Schneider and colleagues reported a significant increase in short chain fatty acids (SCFAs) in 10 enteral-fed patients receiving Saccharomyces boulardii compared with 15 healthy controls ⁴⁷⁾. Saccharomyces boulardii-induced increase of fecal short chain fatty acid concentrations may explain the preventive effects of this yeast on total enteral nutrition (TEN)-induced diarrhea ⁴⁸⁾. In three randomized controlled trials the relative significant reduction in enteral nutrition-related diarrhea in the Saccharomyces boulardii group compared with controls ranged between 5% and 8.2% ⁴⁹⁾. More studies are needed to elucidate the mechanisms of how Saccharomyces boulardii can prevent total enteral nutrition (TEN)-induced diarrhea.

Antibiotic-associated diarrhea

Antibiotic-associated diarrhea is defined as otherwise unexplained diarrhea that occurs in association with the administration of antibiotics ⁵⁰⁾. Measures to prevent antibiotic-associated diarrhea include the use of probiotics. Of the 10 controlled trials in adults using Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea, 8 (80%) showed significant efficacy for the prevention of antibiotic-associated diarrhea ⁵¹⁾. The protective effect of Saccharomyces boulardii and the significant relative reduction in antibiotic-associated diarrhea compared with controls ranged between 7.4% and 25% ⁵²⁾. Other studies failed to demonstrate a significant protective effect of Saccharomyces boulardii and this may be secondary to short or no follow-up after antibiotic exposure ⁵³⁾. Two randomized controlled trials have assessed the ability of Saccharomyces boulardii to prevent antibiotic-associated diarrhea in children and the relative significant increase in prevention of antibiotic-associated diarrhea in the Saccharomyces boulardii group compared with controls ranged between 7.6% and 30.1% ⁵⁴⁾.

A recent meta-analysis of the 10 randomized, controlled trials in adults found that Saccharomyces boulardii was significantly protective for antibiotic-associated diarrhea with a pooled relative risk of 0.47 ⁵⁵⁾. Relative risk or risk ratio (RR) is the ratio of the probability of an event occurring (for example, developing a disease, being injured) in an exposed group to the probability of the event occurring in a comparison, non-exposed group. A relative risk of less than 1 means the event is less likely to occur in the experimental group than in the control group. Finally, in another meta-analysis from five trials involving 1076 subjects, a significantly protective effect of Saccharomyces boulardii was found (pooled RR = 0.43) ⁵⁶⁾. However, although many meta-analyses have concluded that probiotics are effective for preventing antibiotic-associated diarrhea ⁵⁷⁾, most probiotic meta-analyses have focused on one type of disease indication (e.g. antibiotic associated diarrhea) with a variety of probiotic strains. Thus, the summarized data from meta-analyses that are focused only on the use of Saccharomyces boulardii in preventing antibiotic-associated diarrhea and conclude that this probiotic is efficacious for this indication.

HIV-related diarrhea

Patients with HIV-associated diarrhea seem to be one group that requires a higher than typical dose of Saccharomyces boulardii. In a blinded, placebo-controlled study in 11 HIV-positive patients who had chronic diarrhea, lower doses of Saccharomyces boulardii were not as effective compared with 6 patients who reported that diarrhea was controlled while taking 3 g/day Saccharomyces boulardii after 1 month ⁵⁸⁾. In a randomized controlled trial of 35 adult patients with acquired immune deficiency syndrome (AIDS) and chronic diarrhea, 61% of patients given Saccharomyces boulardii had their diarrhea resolved compared with patients on placebo (12%) ⁵⁹⁾. Further confirmation on whether higher doses of Saccharomyces boulardii may benefit patients with HIV-related diarrhea is needed since this observation is based on very limited data.

Crohn’s disease

Recently, the use of probiotics for maintaining remission from active disease in patients with Crohn’s disease was given a ‘C’ recommendation rating level by a panel of experts evaluating the efficacy of the supplements, mostly due to a scarcity of data ⁶⁰⁾. In a small pilot study of 31 patients with Crohn’s disease in remission all patients continued their maintenance medications and were randomized to either Saccharomyces boulardii for 3 months or placebo [Garcia et al. 2008]. Those treated with Saccharomyces boulardii were found to have a significant reduction in colonic permeability compared with those given placebo, thus reducing the risk of bacterial translocation in these patients ⁶¹⁾. Two randomized controlled trials tested Saccharomyces boulardii for patients with Crohn’s disease ⁶²⁾. In a small randomized study of 20 patients with Crohn’s disease all patients continued their maintenance medications and were randomized to either Saccharomyces boulardii for 7 weeks or placebo. Patients treated with Saccharomyces boulardii were significantly improved compared with the placebo group ⁶³⁾. Finally, in a study of 32 patients with Crohn’s disease who were in remission, significantly fewer patients treated with Saccharomyces boulardii (6%) relapsed than the control group (38%) ⁶⁴⁾. Further studies to establish the efficacy of Saccharomyces boulardii in treatment of Crohn’s disease are needed.

Ulcerative colitis

Probiotics have been used as an adjunct treatment in an attempt to induce remission in patients with active ulcerative colitis flares ⁶⁵⁾. In a small pilot study of 25 adults with mild to moderate ulcerative colitis that were treated with a combination of mesalazine and Saccharomyces boulardii for 4 weeks, most (68%) of the patients responded to the probiotic treatment ⁶⁶⁾. This pilot study had a promising result, but the implications were uncertain as patients were treated for only a short time, were not followed up for subsequent disease flare ups, and no control group was included. In a small pilot study of 6 patients with ulcerative colitis, a therapeutic regimen including Saccharomyces boulardii and rifaximin for 3 months seemed effective in preventing early flare ups of ulcerative colitis ⁶⁷⁾. Further controlled studies on a larger number of patients treated for longer periods with this probiotic agent are warranted. Overall, based upon current consensus, the level of evidence for use of probiotics either to maintain remission or induce remission of ulcerative colitis symptoms is presently limited to a ‘C’ rating ⁶⁸⁾.

Irritable bowel syndrome

Recent evidence suggests a role of the microflora in irritable bowel syndrome (IBS) pathogenesis ⁶⁹⁾. A meta-analysis of 20 RCTs including 1404 subjects found a pooled relative risk (RR) for improvement in global IBS symptoms in 14 probiotic treatment arms (RR = 0.77) ⁷⁰⁾. In a double-blind trial of Saccharomyces boulardii versus placebo in the treatment of IBS patients, the probiotic agent significantly improved the quality of life, but did not improve intestinal symptoms ⁷¹⁾. These findings are inconsistent with those reported in double-blind, randomized controlled trials performed earlier in France ⁷²⁾. Along these lines, a recent retrospective analysis suggested that addition of Saccharomyces boulardii to mebeverine can provide superior results in IBS treatment and that the probiotic agent does exert beneficial effects on the quality of life and IBS symptoms ⁷³⁾. More trials using Saccharomyces boulardii for IBS are required to allow solid conclusions for its use in this condition.

Parasitic infections

Little is known about the efficacy of Saccharomyces boulardii against protozoal infections but this probiotic seems to have a beneficial effect in amebiasis, giardiasis and infection with Blastocystis hominis. In adults, co-administration of lyophilized Saccharomyces boulardii with conventional treatment in acute amebic colitis significantly decreased the duration of symptoms and cyst carriage after 4 weeks ⁷⁴⁾. A prospective randomized controlled trial in patients with amebic colitis showed that addition of Saccharomyces boulardii to metronidazole enhanced clearance of cysts and decreased the mean duration of diarrhea, fever and abdominal pain ⁷⁵⁾.

In a small clinical study of symptomatic children with Blastocystis hominis infection Saccharomyces boulardii had potential beneficial effects in symptoms and number of parasites ⁷⁶⁾.

The combination therapy of Saccharomyces boulardii in addition to metronidazole in patients with giardiasis resulted in a disappearance of Giardia cysts 2 weeks after start of the treatment in contrast to 17.1% of patients treated with 10 days metronidazole as monotherapy who still had Giardia lamblia cysts in the stool ⁷⁷⁾. In another clinical trial of 40 children who received tinidazole for giardiasis of 3 or 4 weeks duration, the percentage of children with only one to three bowel movements per day was significantly higher in the Saccharomyces boulardii group compared with the placebo group (65% versus 15%) ⁷⁸⁾. However, all of the studies regarding use of Saccharomyces boulardii for treatment of parasitic infections are small and the reported results need to be confirmed by larger studies.

Saccharomyces boulardii dosage

Saccharomyces boulardii at 5 to 40 billion colony forming units/day may be appropriate given the modest number needed to treat to prevent one case of diarrhea is ten and the likelihood that adverse events are very rare ⁷⁹⁾.

Adults by mouth:

• For diarrhea in people taking antibiotics: 250-500 mg of Saccharomyces boulardii taken 2-4 times daily for up to 2 weeks is most commonly used. In most cases, daily doses do not exceed 1000 mg daily.
• For diarrhea caused by Clostridium difficile: For preventing recurrence, 500 mg of Saccharomyces boulardii twice daily for 4 weeks along with antibiotic treatment has been used.
• For diarrhea caused by Helicobacter pylori: 500-1000 mg of Saccharomyces boulardii daily for 1-4 weeks is most commonly used.
• For diarrhea associated with HIV: 3 grams of Saccharomyces boulardii daily.
• For traveler’s diarrhea: 250-1000 mg of Saccharomyces boulardii daily for 1 month.

Children by mouth:

• For diarrhea in people taking antibiotics: 250 mg of Saccharomyces boulardii once or twice daily for the duration of antibiotics has been used.
• For general diarrhea: For treating acute diarrhea, 250 mg of Saccharomyces boulardii once or twice daily for 5 days has been used. For treating persistent diarrhea, 1750 billion to 175 trillion colony-forming units of Saccharomyces boulardii twice daily for 5 days has been used. For preventing diarrhea in people receiving tube feedings, 500 mg of Saccharomyces boulardii four times daily has been used.
• For rotaviral diarrhea: 200-250 mg of Saccharomyces boulardii twice daily for 5 days has been used.

Saccharomyces boulardii side effects

Although no adverse effects were observed in any of the clinical trials with Saccharomyces boulardii, the administration of Saccharomyces boulardii is not without risk. A recent systematic review documented that probiotic products such as Saccharomyces boulardii, have been shown to increase the risk of complications in specific patient groups such as immunocompromised subjects ⁸⁰⁾. Saccharomyces fungemia is the most severe complication secondary to administration of the probiotic especially in patients with severe general or intestinal disease who had an indwelling catheter ⁸¹⁾.

Up to now, almost 100 cases of Saccharomyces boulardii-associated fungemia have been reported ⁸²⁾. The origin of the fungemia is thought to be either a digestive tract translocation or a contamination of the central venous line by the colonized hands of health workers ⁸³⁾. Indeed, the simple act of opening a packet of Saccharomyces boulardii can produce air contamination that may pose environmental risk especially for immunocompromised patients ⁸⁴⁾. Once the diagnosis is made, fungemia with Saccharomyces boulardii can effectively be treated with antimycotic medication, although treatment failure with fluconazole has been reported ⁸⁵⁾.

A rare gastrointestinal allergic reaction was also recently reported after Saccharomyces boulardii was given to an infant with a prior diagnosis of food protein-induced enterocolitis syndrome ⁸⁶⁾.

Pregnancy and breast-feeding: There is not enough reliable information about the safety of taking Saccharomyces boulardii if you are pregnant or breast feeding. Stay on the safe side and avoid use.

Overall, Saccharomyces boulardii is safe for use in otherwise healthy populations and fungemia with Saccharomyces boulardii has not been reported, to the best of the authors’ knowledge, in immunocompetent patients ⁸⁷⁾. Caution should be taken in patients with risk factors for adverse events (e.g. patients with central venous catheters or increased bacterial translocation) ⁸⁸⁾. Institutional guidelines are needed to address the potential safety issues related to Saccharomyces boulardii use ⁸⁹⁾.