Living microorganisms are widely used for several therapeutic purposes and their beneficial effects as biotherapeutic agents are well known. While certain strains of lactic acid bacteria and bifidobacteria are used as probiotics in pharmaceutical preparations, feed additives and so-called functional foods yeasts also possess some medicinal efficiency.
The beneficial properties of strains of some Saccharomyces spp are well documented (Rodrigues et al. 1996). In addition to their nutritive value (e.g. provision of vitamins of the B group), probiotic yeasts are generally resistant to gastrointestinal passage and are resistant to most antibiotics. Yeast preparations have also been successfully applied, in combination with antibiotics, to treat Clostridium difficile -related diarrhoea commonly known as antibiotic associated diarrhoea. Probiotic Saccharomyces spp may also help to re-establish a normal gut function after long term antibiotic therapy (McFarland et al., 1994).
Some Saccharomyces spp also have a protective effect, and specific activities, against various enteric pathogens. Saccharomyces spp stimulate sIgA production and the phagocytic system of gnotobiotic mice (Rodrigues et al., 2000). These probiotic yeasts may also have efficacy in the prevention of Traveler's diarrhoea.
Strains of so-called Saccharomyces boulardii, taxonomic status some what unclear since recent work suggests it is a subspecies of Saccharomyces cerevisiae, are regarded as the most prominent representatives of probiotic yeasts within the community of biotherapeutic S. cerevisiae strains. Today, a considerable number of pharmaceutical preparations (capsules, powders, tablets, pellets) containing probiotic yeasts ( Saccharomyces spp ) cells are commercially available, and are marketed mainly via pharmacies and health stores.
We prefer to use the term biotherapeutic agent rather than probiotic because it denotes a microorganism having therapeutic properties (McFarland, 1996).
Biotherapeutic agents, as with probiotics, must be given in sufficient concentration to exert therapeutic properties, remain stable and viable before use and survive in the intestinal ecosystem of the host to exert their therapeutic properties.
2. Biotherapeutic properties of Saccharomyces spp
The genus Saccharomyces has 16 species, including S. cerevisiae and S. boulardii; of which two , S. cerevisiae and S. boulardii, are described in the literature as containing biotherapeutic agents. These strains have been reported to be efficacious in the prevention or recurrence of different types of diarrhoea and colitis in humans (Surawicz et al ., 1989). S.cerevisiae and S.boulardii, have been reported to be effective in the treatment of acute diarrhoea in children (Cetina and Siemo et al ., 1999) and critically ill tube fed patients. S.cerevisiae and S.boulardii release polyamines which help in repairing mucous membranes. These polyamines increase the activity of short chain fatty acids (SCFA) and disaccharide enzymes (lactase, maltase, sucrase). Polyamines stimulate the repair of intestinal cells and the growth of colonic mucosa (Buts et al ., 1994).
S.boulardii is generally administered in lyophilized powder and its application as a food additive has only been reported in a limited number of cases such as in the fermentation of vegetables (Sindhu and Khetarpaul, 2002) and incorporation into commercial yogurts (Lourens and Viljoen , 2001). S. cerevisiae and S. boulardii are unique organisms that have the ability to survive in gastric acidity and are not adversely affected or inhibited by antibiotics. They do not appear to alter or adversely affect the normal flora of the GI tract and can be consumed with normal probiotic bacteria (Elmer and McFarland 2001). Inclusion of S.boulardii and S.cerevisiae in the standard medical treatment for Clostridium difficile infection has been reported to reduce the risk of recurrence in patients experiencing renewed infection (Aloysins et al., 2005).
Children receiving S.boulardii and lactobacilli had a gradual reduction in the number of daily stools, more noticeable after the first day of treatment compared to those in a placebo group. Patients treated with S.boulardii and lactobacilli had a significant faster recovery compared with a placebo control. and Lactobacillus spp. were found to be similarly effective in decreasing the duration of diarrhea (Gaon et al .,2003). Lactobacilli appear to enhance the beneficial effects of Saccharomyces boulardii on intestinal mucosa (Buts, 1999). A meta-analysis by Aloysins et al., 2005 suggests that S.boulardii and Lactobacilli can be used to prevent antibiotic associated diarrhea. S.cerevisiae may also have value in the treatment of C.difficile associated diarrhea (Martins et al ., 2005). S. cerevisiae can also deliver vitamin B and other nutrients like selenium and chromium. S. boulardii
3. Mechanism of controlling pathogenic organisms by probiotic yeast
S.cerevisiae and S.boulardii share a common mechanism of action against pathogenic bacteria.
Pharmacokinetics is the study of the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Pharmacokinetics is a branch of pharmacology dedicated to the study of the time course of substances and their relationship with an organism or system. In practice, this discipline is applied mainly to drug substances, though in principle it concerns itself with all manner of compounds residing within an organism or system, such as nutrients, metabolites, endogenous hormones, and toxins.
S.cerevisiae and S. boulardii can resist gastric acidity, proteolysis and are able to achieve and maintain high populations in the GI tract. They can permanently colonise the colon and do not easily translocate out of the intestinal tract (Boddy et al ., 1991). They can also be detected alive throughout the digestive system, if they are given daily in freeze dried form (WHO.,1995). In gnotobiotic mice, a single dose of S. boulardii was found to result in colonization of the intestinal tract, the yeast being detectable at a constant, albeit low, level (10 7 c.f.u./g) for 60 days. In healthy human volunteers, that received a single oral dose of 1 g S. boulardii , it took 36 to 60 hours to reach maximum yeast numbers, 2 to 5 days to decline to no-detectable concentrations. S.cerevisiae and S. boulardii are sensitive to non-absorbable antimycotics such as nystatine but can safely be administered with re-absorbable antifungal agents such as fluconazole.
Pharmacodynamics is the study of the biochemical and physiological effects of drugs, the mechanisms of drug action and the relationship between drug concentration and effect. Pharmacodynamics is the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug .
The pharmacodynamics of S.cerevisiae and S.boulardii involves 3 different aspects.
A. Direct antagonism
S.boulardii reduces the growth of Clostridium albicans, Escherichia coli, Salmonella typhi, Shigella dysenteriae, Vibrio cholerae, Salmonella enteritidis (Czerucka and Rampal 2002), and Clostridium difficile (Izadnia et al ., 1998). S.cerevisiae reduces the growth of E. coli , Shigella flexnerii, Clostridium difficile and Vibrio cholerae.
S.cerevisiae and S.boulardii have been shown to protect against various enteric pathogens and members of the family Enterobacteriaceae in animal studies (Czerucka and Rampal 2002).
B. An antisecretory effect by acting specifically on the binding of toxins to intestinal receptors
Pathogenic strains of C. difficile produce two well-characterized toxins, A and B, that cause mucosal damage and inflammation of the colon (Pothoulakis and Lamont 2001). S.cerevisiae and S. boulardii significantly reduce the liquid secretion and mannitol permeability caused by C. difficile toxin A in the rat ileum, compared to controls (Pothoulakis 1993). Chromatography of filtered supernatant from S.boulardii led to the identification of an active fraction that decrease toxin A-induced rat ileal secretion by 46%, intestinal permeability by 74% and prevented toxin A-mediated inflammation and villus damage. It was demonstrated that this fraction was enriched in a protease that acted on the toxin A molecule and inhibited toxin A binding to its receptor on the brush border membrane of rat intestinal cells (Pothoulakis et al., 1993). This protease was identified as a 54-kDa serine protease (Castagliuolo,1996). The amount of cholera toxin-stimulated cAMP (cyclic adenosine monophosphate) was also decreased by 50% in cells treated by S. boulardii and cholera toxin compared to cells exposed to the toxin alone.
C. Trophic effect on the enterocyte with stimulation of enzymatic expression and intestinal defense mechanism
Rats treated with Saccharomyces spp showed significant increases in sucrase-isomaltase, lactase and maltase activities. In their study on human volunteers (Jahn et al ., 1996) used an in situ technique to measure brush border enzyme activities in snap-frozen biopsies. After treatment with S.cerevisiae and S. boulardii , an increase in lactase, glycosidase and alkaline phosphatase activity was detected both at the basal and apical parts of villi, with increases ranging from 22 to 55 % compared to the basal activities measured before treatment. S.cerevisiae and S. boulardii, b oth in humans and in a rat model, were found to enhance the expression of disaccharidases and alkaline phosphatase enzymes. This effect may improve the absorption of carbohydrates, usually defective in acute and chronic diarrheal disorders. S. cerevisiae and S. boulardii contain polyamines (spermine and spermidine which have the same trophic effect on the intestinal mucosa, with an increase in diasaccharidase activity, as an equivalent amount of spermine and spermidine given to test animals (Buts,1994; Balasundram et al ., 1994). The overall mechanism of controlling pathogenic organisms by biotherapeutic yeasts is shown in figure 1.
4. Occurrence of Saccharomyces spp in milk and milk products
Saccharomyces spp e.g. S. burnetii, S. kluveri, S. byanus, S. rosinii, S. cerevisiae and S. boulardii may be isolated from a variety of dairy products including milk, yogurt ,cream, dahi, cheese and kefir. Yeasts rarely grow in milk stored at refrigeration temperature because they are out-grown by psychotropic bacteria. However, in sterilized milk in the absence of competition, Saccharomyces spp are capable of growth to populations of 10 8 -10 9 cfu/ml. Saccharomyces spp. are often present in soft mould ripened cheeses and semi-hard and hard cheeses including Cheddar. Growth of Saccharomyces spp in cheeses is thought to be related to its ability to use lipid and protein products form other species and possibly their ability to utilise lactic acid present in the cheese (Robinson, 2000).
5. Development of yeast based fermented milk products
The frequent occurrence of yeasts in dairy and related products indicate their ability to metabolize milk constituents. Saccharomyces spp cannot ferment lactose so they develop in milk as a secondary flora, after bacterial growth. Lactic acid bacteria (LAB) ferment milk lactose through hydrolysis to glucose and galactose. The glucose moiety is fermented to lactic acid. Lactic acid creates a high acid environment, however, the ability of some yeasts to utilize lactic acid as a carbon source can create a selective environment for yeast growth (Fleet, 1990) and for the growth of less acid tolerant lactic acid bacteria.
Fermented milk products that are manufactured using starter cultures containing yeasts include acidophilus-yeast milk (Lang and Lang 1975), Kefir, Koumiss and Leban. S.boulardii is capable of utilizing the yogurt constituents as growth substrates and maintaining cell counts exceeding 10 6 cfu/ml (Lourens and Viljoen , 2001). Various yeast based fermented milk products and their characteristics are shown in table 1.
Table 1. Characteristics of yeast-based fermented milk products
Fermented milk products
Microorganisms responsible for the fermentation process
Description of the products
Lactic acid bacteria, Acetic acid bacteria and yeasts (Lactose fermenting and non lactose fermenting)
A mixed lactic acid and alcoholic fermentation.
L.bulgaricus and S.cerevisiae
The mare or camel fermented milk of a mare or camel milk. It may be mildly alcoholic
L.bulgaricus, S.thermophilus and yeasts
A concentrated yogurt like product.
Acidophilus yeast milk
L.acidophilus and S.cerevisiae
Acidic and alcoholic product with probiotic properties
S. lactis var. hollandicus and Saccharomyces taette
Moderately ropy and sour milk product of slightly flowing consistency that contains not more than 0.3%-0. 5% of alcohol
6. Safety of probiotic yeasts
This area has been reviewed by Boyle et al. (2006). The evidence suggests that providing consumers are not immunocompromised or seriously ill there is little risk.
Saccharomyces spp are emerging as potential probiotic organisms. Already there is a marked increase in the sale of various yeast based probiotic products. However there is a need to isolate more potential probiotic strains of Saccharomyces and to develop new probiotic yeast based dairy products. Using probiotic Saccharomyces spp alone or in combination with lactic acid bacteria can enhance the nutritive value of fermented dairy products.
8. Probiotic and prebiotic reference list
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How to cite this article
Dixit, Kalpana and Gandhi, D.N. (2006) .
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