Unique Properties of Yeast Probiotic Saccharomyces boulardii CNCM I-745: A Narrative Review

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 rolein 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.


Introduction And Background
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.

FIGURE 1: Advantages of yeasts as probiotics
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.

Review
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.

History of probiotics
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].

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

Sources of probiotics
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].

Properties of an ideal probiotic
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 as a probiotic
Yeast probiotics with some unique properties have an edge over bacterial probiotics and the differences between them are listed in Table 1.

Possible implications of the difference between yeast and bacterial probiotic properties
The difference between yeast and bacterial probiotic properties and their possible implications are mentioned in Table 2.

Properties Comments
Steric hindrance [16] Yeast cells, due to their ~10 times larger size than bacteria, provide a steric hindrance against pathogenic bacteria.It increases the prospect of yeast being a probiotic agent Immune response [17] The cells of yeast contain many immunomodulatory components The outer layer of the cell wall consists of Mannoproteins that bind dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), Tolllike receptor 4 (TLR4), and others The middle layer contains β-glucans which bind Dectin-1 and TLRs 2 and 6 The innermost wall layer contains chitin, which binds the mannose receptor Different sites of action in the GI tract [15] Yeast is found both in the stomach and colon, suggesting their ability to survive in such different conditions (resistance to pH variation, tolerance of stress).This suggests that yeast is a good candidate as a probiotic because probiotics entering the GI tract must be resistant to variations in the pH Resistance to antibiotics [15] Bacteria can transfer the resistance genes to pathogenic bacteria, leading to antibiotic resistance transfer of genetic material which is not possible between bacteria and yeast, making yeast a potential candidate as a probiotic for the prevention of antibiotic resistance Autoaggregation [16] The ability of yeast strains to self-aggregate and produce flocs is the autoaggregation property This is a survival response in the presence of adverse environmental conditions like the human GI tract This provides a competitive advantage to the yeast cell over other microorganisms, including enteric bacteria Because, as compared to the bacteria, the yeast cells are larger and heavier, they sediment faster and in a larger amount

Properties of S. boulardii CNCM I-745
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,

FIGURE 3: Unique properties of S. boulardii CNCM I-745
Image Credits: All authors

Mechanism of action of S. boulardii as a probiotic
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].

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

Safety of S. boulardii
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].

Conclusions
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.

FIGURE 4 :
FIGURE 4: Different potential mechanisms of action of Saccharomyces boulardii 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.

TABLE 4 : 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.