Review began 08/22/2023 Review ended 09/26/2023 Published 10/01/2023

© Copyright 2023 Gopalan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CCBY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Sarath Gopalan , Sridhar Ganapathy , Monjori Mitra , Neha . , Devesh Kumar Joshi , Krishna C. Veligandla , Rahul Rathod , Bhavesh P. Kotak

1. Pediatrics, Madhukar Rainbow Children's Hospital, New Delhi, IND 2. Pediatrics, Janani Children's Hospital, Mumbai, IND 3. Pediatrics, Institute of Child Health (ICH), Kolkata, IND 4. Medical Affairs, Dr. Reddy's Laboratories Ltd., Hyderabad, IND 5. Medical Affairs, Dr. Reddy’s Laboratories Ltd., Hyderabad, IND 6. Ideation and Clinical Research/Medical Affairs, Dr. Reddy’s Laboratories Ltd., Hyderabad, IND

Corresponding author: Neha ., [email protected]

Probiotics, both bacterial and yeast, have long been associated with a beneficial health history and human well-being. Among yeasts, Saccharomyces is a genus that is efficacious in rendering better human health, with Saccharomyces boulardii (S. boulardii) CNCM I-745 being classified as a probiotic agent. The present review highlights the unique properties of S. boulardii and its role in the prevention of antibiotic-associated diarrhea (AAD) and pediatric acute gastroenteritis (PAGE) in comparison to bacterial probiotics. Its unique properties, such as viability over a wide pH range, inability to acquire antibiotic resistance genes, and property to achieve a steady state rapidly, have given S. boulardii an edge over bacterial probiotics. In AAD patients, prophylactic use of S. boulardii has shown a significantly lower risk of AAD (in comparison to controls) and restored the diversity of gut microbiota. Among Indian children with PAGE, S. boulardii CNCM I-745 was found superior to Lactobacillus rhamnosus GG and four strains of Bacillus clausii in shortening the duration of diarrhea and reducing the length of hospital stay. S. boulardii CNCM I-745 being considered a safe probiotic for use in children and adults also finds recommendations in several international guidelines for the management of acute diarrhea. The current review discusses evidence for the proven efficacy and safety of S. boulardii CNCM I-745 as a probiotic for preventing gastrointestinal disorders.

Categories: Gastroenterology Keywords: cncm i-745, paediatric acute gastroenteritis, antibiotic-associated diarrhoea, saccharomyces boulardii, probiotic

The gut microbiome is invoked as a contributor to gastrointestinal (GI) ailments and a broad range of chronic human conditions, including cancer and diseases with inflammatory, metabolic, cardiovascular, autoimmune, neurologic, and psychiatric components [1,2]. Microbial dysbiosis is an imbalance of the structure and function of the gut intestinal microbiota, which is quite common in today’s World. Changes in diet, bacterial infections, and indiscriminate use of antibiotics are the common causes of dysbiosis [3].

One of the most efficient ways to restore gut microbial balance is probiotics [3]. Probiotic is a Greek term meaning “for life”. It is defined by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host" [4,5]. There has been abundant research with probiotics of bacterial origin but limited work with probiotics of yeast origin. One of the rising threats of concern with probiotics of bacterial origin is their capability to transfer the resistant gene to pathogenic bacteria. This is where yeasts, which are naturally resistant to antibacterial agents, play a useful and important role as probiotics [6]. The other advantages of probiotics of yeast origin are demonstrated in Figure 1.

How to cite this article Gopalan S, Ganapathy S, Mitra M, et al. (October 01, 2023) Unique Properties of Yeast Probiotic Saccharomyces boulardii CNCM I-745: A Narrative Review. Cureus 15(10): e46314. DOI 10.7759/cureus.46314

Adapted from Shruthi et al., 2022 [6] (CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/))

The yeast S. boulardii CNCM I-745 was the first yeast probiotic that was studied for the management of clinical disorders in humans. The S. boulardii strain is stable over a wide range of temperature levels and pH (including acidic conditions). It does not promote antibiotic resistance and has a beneficial effect against infections caused by pathogenic bacteria (e.g., Clostridium difficile, Salmonella, Shigella, Escherichia coli), viruses, and yeasts (mainly Candida albicans). Evidence supports the use of S. boulardii CNCM I-745 for treating several diseases [7].

The present review summarizes the current evidence on the role of S. boulardii as a biotherapeutic agent for the prevention of various GI diseases like antibiotic-associated diarrhea (AAD) and gut dysbiosis.

PubMed and NCBI databases were used for the search of the articles using the following keywords: probiotics, yeast as probiotics, and advantages of probiotics.

Open-access articles discussing the advantages of various yeast strains as probiotics were included in the review.

Elie Metchnikoff, a Nobel laureate, was the first to report the beneficial effect of probiotics on human health. He suggested that lactobacilli may be considered a probiotic with a positive impact on health and the prevention of aging [4].

Some beneficial effects of probiotics on human health are mentioned in Figure 2.

Adapted from Celebioglu et al., 2018 [8]. (Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/))

GI: Gastrointestinal

Probiotic bacteria have been obtained from a variety of sources, including human breast milk, diets containing both plants and meat, human and animal feces, and animal guts [9]. Another source of probiotics is the human GI tract. From this source, several of the probiotic strains such as Lactobacillus gasseri and L. reuteri used today have been isolated. Besides, many animal species, including pigs, rats, and even poultry, have intestines that are rich in probiotics [10]. Also, several bacterial, fungal, and archaeal species are abundantly found in the human microbiome [11].

The probiotic strains act differently against different pathogens by various actions. They act by directly killing or inhibiting specific pathogens, destroying pathogenic toxins, and reinforcing the host cell integrity. They also prevent the attachment of pathogen-host cells, restore the normal microflora, and balance the immune response (up or down-regulation).

All probiotics do not possess all of these mechanisms, but probiotics, such as S. boulardii CNCM I-745, are found to possess multiple anti-pathogen properties [12,13]. S. boulardii possesses several mechanisms of action (Figure 2) which can be divided into three main types, namely, luminal action, trophic action, and mucosal-anti-inflammatory signaling effects. S. boulardii in the intestinal lumen, might aid in interfering with pathogenic toxins and their attachment, interacting with normal microbiota, preserving cellular physiology, or re-establishing short-chain fatty acid levels. In addition, S. boulardii may also regulate the immune system, both within the lumen and systemically [14].

Yeast probiotics with some unique properties have an edge over bacterial probiotics and the differences between them are listed in Table 1.

1. TABLE 1: Difference between bacteria and yeast and its implication on probiotics PPM: Phosphopeptidomannan; PLM: Phospholipomannan; LPS: Lipopolysaccharide; LTA: Lipoteichoic acid
2. TABLE 2: Possible implications of the difference between yeast and bacterial probiotic properties GI: Gastrointestinal

S. boulardii CNCM I-745 is a probiotic yeast of choice for the management of AAD and pediatric acute gastroenteritis (PAGE). Henri Boulard (French microbiologist) discovered S. boulardii CNCM I-745 in 1923, and it belongs to the S. cerevisiae species [18]. Due to its ability to produce different bioactive compounds, S. boulardii has taken a key position in the scientific community and is recently being used for managing gut diseases. Clinical evidence suggests that oral administration of S. boulardii is beneficial in managing multiple GI diseases including traveler’s diarrhea, AAD, C. difficile-associated syndrome, irritable bowel syndrome, and Crohn’s disease [19]. Due to the excessive use of antimicrobials, a continuous rise in multidrug-resistant organisms is reported. Therefore, in managing antibiotic resistance, probiotics,

Image Credits: All authors

The gut microbiome performs a variety of functions, such as preventing pathogen colonization, maintaining the epithelial barrier, and controlling immune response [22]. S. boulardii similarly as a part of its probiotic effect has various modes of action like immunological and anti-toxin effects, modulation of intestinal flora, and impact on enzyme activity (Figure 4) [22].

Image Credits: All authors

On the left various effects of different pathogenic microbes are shown. On the right, seven different protective effects of S. boulardii are mentioned. Within the lumen of the intestine, S. boulardii may degrade toxins of pathogens, interfere with pathogenic adherence, modulate normal microbiota, and preserve normal intestinal physiology. S. boulardii may also indirectly restore normal SCFA balance and increase secretory IgA levels or act as an immune regulator by influencing cytokine levels.

LPS: Lipopolysaccharide; Sb: S. boulardii.

Clinical evidence demonstrating the role of S. boulardii in the management of AAD and PAGE is given in Table 3.

S. boulardii for the prevention of AAD

McFarland et al./ Metaanalysis, 10 randomized controlled trials (RCTs) [14]

McFarland et al./ Metaanalysis 22 trials (23 treatment arms) [23]

Jindal et al./

Adults on antibiotics (n

= 1869)

Children (n =

4155) on antibiotics

Children (n = 300, age 6 months-12 years) with

S. boulardii (200 mg – 1000 mg /day)

A significant therapeutic efficacy ofS. boulardii in preventing AAD was reported (RR = 0.47, 95% CI: 0.35-0.63, P<0.001)

Twelve trials tested a single strain of probiotic and 10 trials tested a mixture of probiotic strains

Analysis among single strains trials (12 trials) showed that S. boulardii significantly reduced AAD (pooled RR = 0.43, 95% CI: 0.32-0.60). All the probiotics were safe

Randomised, open, parallel study [24]

upper respiratory tract infection or urinary tract infection receiving antibiotics

Control group: Antibiotic test group: Antibiotic +S. boulardii [BASE] 250 mg B.D.

Szajewska et al./ Systematic review with metaanalysis, 21 RCTs [25]

Children and adults (n = 4780) receiving antibiotics for any reason, including Helicobacter pylori eradication therapy

Control group: Antibiotic + placebo/no treatment Experimental group: Antibiotic + S. boulardii at any dose/ duration

Yang et al./ Metaanalysis, 21 studies [26]

Children (n = 3534 patients) on antibiotics

S. boulardii

S. boulardii for the management of PAGE

A significant reduction in the incidence of diarrhea was observed in patients who received S. boulardii (P<0.001)

Among patients treated with antibiotics, a reduced risk of AAD was observed in the S. boulardii group vs placebo or no treatment, from 18.7% to 8.5% S. boulardii reduced the risk of diarrhea in children from 20.9% to 8.8% and in adults from 17.4% to 8.2% In children, S. boulardii also reduced the risk of C. difficile-associated diarrhea

For the prevention of AAD, the S. boulardii group could significantly reduce the diarrhea rate vs the control group In a Meta-analysis of 7 studies (523 patients), the S. boulardii group demonstrated a significantly higher efficacy rate in preventing AAD vs the control group

Padayachee et al./ Systematic review = 10 studies; Metaanalysis, 5

1. RCTs [27]
2. RCTs [28]

Children (n = 4217, aged 1 month to 15 years)

S. boulardii vs placebo or no intervention

Ragavan et al./ Retrospective analysis [29]

Indian children (n = 160, age: 0 to 18 years) with acute diarrhea

Oral rehydration solution and zinc with or withoutS. boulardii CNCM I-745 (250 mg twice daily)

McFarland et al./ A systematic Treatment for Five single-strain probiotics and 3 multi-strained

mixtures (Strains studied include S. boulardii CNCM

S. boulardii was reported to be efficacious at a daily dose <300 mg/d (5 RCTs, n = 873, mean difference (MD) −0.84 d; high heterogeneity I2 = 91%; or 500 mg/d (15 RCTs, n = 2248, MD −0.86 d; I2 = 58%); or >500 mg/d (1 RCT, n = 41, MD −2.76 d) For those treated with S. boulardii compared with the control group, reduced duration of hospitalization (8 RCTs, n = 999, MD −0.85 d, 95% CI −1.35 to −0.34; I2 = 91%) was reported On day 2 to day 7 of treatment, S. boulardii reduced the risk of diarrhea Adverse effects were comparable between the groups

In the S. boulardii group, the median duration of diarrhea post-treatment was significantly shorter (3 days) vs the non- S. boulardii group (4 days) In the S. boulardii group, a significant reduction in the frequency of stools was observed posttreatment (1.7 vs 2.5 in the nonS. boulardii group).

S. boulardii CNCM I-745 had the strongest effect on shortening the duration of diarrhea (standardized mean difference, –1.86 d; 95% CI, – 2.8 to –0.9), S. boulardii and L. rhamnosus GG

review (22 RCTs) and meta-analysis (17 RCTs)

1. [30]
2. [31]

Children with acute gastroenteritis (n = 1282, aged <5 years)

S. boulardii vs control

S. boulardii could effectively shorten diarrhea duration (MD = 19.70, 95% CI, -24.87, 14.52) and reduce the length of hospital stay (MD = −0.91, 95% CI: -1.28, -0.54) A significantly lower relative risk of continued diarrhea was observed in the treatment group after 1-day treatment (RR = −0.31, 95% CI, 0.59, 0.03) and 3 days of treatment (RR = 0.52, 95% CI: 0.41, 0.66) vs the control group After 3 days of treatment, S. boulardii reduced the average number of diarrhea by about 1.03 (MD= −1:03, 95% CI: -1.53, -0.53) No adverse drug reactions were reported in either group

S. boulardii vs other probiotics for management of AAD and PAGE

McFarland et al./ metaanalysis [32]

Children on antibiotics

Sixteen different types of probiotics were combined

S. boulardii and L. rhamnosus displayed significant efficacy for pediatric AAD when pooled (pooled RR 0.43, 95% CI 0.21-0.86).

Vineeth et al. [33]

Indian children suffering from rotaviral diarrhea (n = 80)

The average dose ofS. boulardii (500 mg/day) vs B. clausii (10 mL/day)

In the S. boulardii group, the total mean duration of diarrhea was significantly shorter vs the B. clausii group

Blaabjerg et al./ Systematic review and metaanalysis, 17 RCTs [34]

Outpatients of all ages on antibiotics (n

= 3631)

Lactobacilli spp., Lactococcus spp., Streptococcus spp. Bifidobacterium spp., Saccharomyces spp., Leuconostoc cremoris, Bacillus spp., Clostridium spp., or alone or in combination

In a subgroup analysis, S. boulardii (four studies) showed a significantly lower risk of AAD vs control (RR 0.41; 95% CI 0.30 to 0.57), while this was not observed in the combination of L. acidophilus La-5 and B. lactis Bb-12 (2 studies) (RR 0.79; 95% CI 0.47 to 1.33)

Vidjeadevan et al./ RCT [35]

Children (n = 105, aged 636 months) with acute diarrhea

Group A received ORS and zinc; Group B received ORS, zinc and S. boulardii; Group C received ORS, zinc, and B. clausii

The mean duration of diarrhea was 108 hours for group A, while 72 hours and 96 hours for group B and group C, respectively. The mean duration of diarrhea was highest in group A (108 hours) and lowest in group B (72 hours)

Johnston et al./ Cochrane review, 33 studies [36]

Children receiving antibiotics (0 to 18 years, n

= 6352 participants)

Probiotics assessed included Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., or Streptococcus spp., alone or in combination, placebo or no treatment

Among various probiotics, placebo or no treatment, L. rhamnosus or S. boulardii at 5 to 40 billion colony forming units/day were the most appropriate probiotics for the prevention of AAD

Li et al./ Bayesian network Meta-analysis (21 interventions) [37]

Children with acute diarrhea (n = 13,443)

Children (n =

Probiotic interventions could be divided into singlestrain and multi-strain probiotics. The single-strain probiotics included S. boulardii, L. rhamnosus GG, L. reuteri, B. clausii, L. acidophilus, B. lactis, L. sporogenes, L. plantarum, E. coli Nissle 1917 (ECN 1917), L. paracasei, and E. faecium.Multiple-strain probiotics included L. species (spp.), L. spp. + B. spp., L. spp. + B. spp.+ S. spp., L. spp. + S. spp., B. spp. + S. spp., Bacillus spp. + E. spp. + Clostridium spp., L. spp. + B. spp. + E. spp., L. spp. + B. spp. + Pediococcus spp., and L. spp. + S. spp. + C. spp. + Bacillus spp. Control arm: Placebo/no treatment

S. boulardii among all the probiotics was the most effective in reducing both duration of diarrhea (vs placebo) and the risk of diarrhea lasting ≥2 days (vs placebo or no treatment). It [Odds ratio (OR) = 0.22; 95%CI, 0.11, 0.41] significantly decreased the risk of diarrhea lasting ≥2 days versus placebo or no treatment

1. TABLE 3: S. boulardii in the management of AAD and PAGE AAD: Antibiotic-associated diarrhea; PAGE: Pediatric acute gastroenteritis

A recent study reports that the probiotic E. coli strain Nissle 1917 produces in vitro and in vivo colibactin and subsequently induces mutagenic DNA damage. This is a serious safety concern that should not be ignored keeping in mind the health of patients and the general public overall [39]. As the genotoxic activity of this strain cannot be dissociated from its probiotic activity, the safety aspects of large-scale use of this probiotic strain need to be reassessed. This brings up an important issue of side effects that may be associated with any effective probiotic [40].

S. boulardii CNCM I-745 is considered to be a safe probiotic. Clinical trials have not reported any side effects with S. boulardii [19]. Very rarely, in critically ill and/or immunocompromised patients, increased amounts of S. cerevisiae infections (fungemia) have been observed [41]. For immunocompromised patients, even opening a packet of S. boulardii can lead to air contamination, increasing the risk of infection [42]. However, metaanalysis has reported S. boulardii to be safe in children suffering from acute diarrhea [43].

Table 4 provides the global recommendations for S. boulardii as a probiotic.

Abbreviations- IAP: Indian Academy of Paediatrics; ESPGHAN: European Society for Paediatric Gastroenterology; Hepatology, and Nutrition AAD: Antibiotic-associated diarrhea; AGE: Acute gastroenteritis; HP: Helicobacter pylori.

Probiotic S. boulardii CNCM I-745, by its unique properties, acts in a variety of ways to exert its pathogen-

binding, immunological, and anti-toxin actions. Additionally, it cannot transfer genetic material, making it a potential candidate as a probiotic for preventing antibiotic resistance. S. boulardii stands out among the other probiotics as one of the most effective for avoiding AAD in children. In comparison to L. rhamnosus GG and a few strains of B. clausii, S. boulardii CNCM I-745 shows a significantly reduced mean duration of diarrhea in PAGE patients. Furthermore, because of its proven efficacy and safety, it is recommended by ESPGHAN and other global bodies for the prevention and treatment of acute diarrhea. Thus, S. boulardii CNCM I-745 is one of the preferred choices of probiotics for the management of AAD and PAGE due to its distinct advantages over bacterial probiotics as well as its favorable efficacy and safety profile.