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Abstract
The effect of S. boulardii on experimental colitis induced by the single oral administration of 1 mg/kg of clindamycin in the Syrian hamster was studied. Oral administration of S. boulardii for 13 days, starting 3 days prior to the administration of clindamycin, significantly reduced the mortality rate and inhibited the growth of C. difficile in the caecum and colon. There was a marked improvement in the sub-mucosa and mucosa which showed major inflammatory lesions when clindamycin was administered alone.
... Viable lactobacilli failed to prevent or change the duration or symptoms of enterotoxic Escherichia coli diarrhea in adults [27]. Viable Lactobacillus acidophilus preparations are not effective in the prevention of travelers' diarrhea [28,29], although enterotoxic Escherichia coli is the most important (40%) causal organism [30]. Lactobacillus salivarius inhibits colonization of the stomach with Helicobacter pylori in gnotobiotic BALB/c and germ-free mice [31]. ...
... The same combination also failed to show any effect in the prevention of travelers' diarrhea, antibiotic-associated diarrhea and enteral feeding-associated diarrhea [28,37,38]. Viable Lactobacillus acidophilus was tested, without success, in the prevention of travelers' diarrhea [29,39]. A heat-killed Lactobacillus acidophilus strain was evaluated in a double-blind placebo-controlled study in the treatment of acute diarrhea [40]. ...
... In vitro, it has been demonstrated that the protease of 54 kDa digests both toxin A and the receptor on the enterocyte [28]. In vivo, Saccharomyces boulardii decreases the mortality rate, the quantity of toxin A and the intestinal lesions caused by Clostridium difficile [29,30]. ...
Treatment of acute infectious gastroenteritis consists mainly of rehydration and rapid realimentation. However, the natural intestinal microflora is disrupted in both acute and chronic infectious diarrhea, resulting in complex interactions possibly aggravating this frequently self-limiting condition. Therefore, additional therapeutic intervention with biotherapeutic agents is worth considering. The results of most randomized prospective double-blind clinical trials with bacterial biotherapeutic agents are disappointing, showing a lack of efficacy, except for Lactobacillus casei strain GG, for which both positive and negative results have been published.
... Still, there is also evidence that this yeast can occasionally cause superficial and systemic infections [233][234][235]. The related strain Saccharomyces cerevisiae boulardii is used clinically as a probiotic and as a preventive measure against Clostridium difficile infection [236,237]. Jiang et al. documented a protective role of S. cerevisiae in mice against inflammatory disorders by the replacement of enteric bacteria [221]. Furthermore, S. cerevisiae was shown to be able to reduce intestinal translocation of enterotoxigenic E. coli (ETEC) and modulate the mucosal immunity in pigs [238]. ...
... To this date, the optimal and most beneficial composition of such a transplant is yet to be determined. As mentioned above, Massot et al. described that S. cerevisiae boulardii reduced C. difficile growth in hamsters [236]. The potential beneficial role of this fungus was also implied by studies in mice that successfully used S. cerevisiae boulardii to reduce C. difficile-induced mortality [241]. ...
Fungi and bacteria encounter each other in various niches of the human body. There, they interact directly with one another or indirectly via the host response. In both cases, interactions can affect host health and disease. In the present review, we summarized current knowledge on fungal-bacterial interactions during their commensal and pathogenic lifestyle. We focus on distinct mucosal niches: the oral cavity, lung, gut, and vagina. In addition, we describe interactions during bloodstream and wound infections and the possible consequences for the human host.
... The probiotic yeast Saccharomyces boulardii has been investigated as a potential exogenously administered agent for maintaining colonization resistance during antibiotic therapy. 101 S. boulardii decreased C. difficile associated cecitis and death in hamsters 101,102 and antibiotic associated diarrhea in humans. 103 A hamster model of recurrent C. difficile was described by Elmer et al. 38 The authors suggested that S. boulardii administration may help prevent extensive overgrowth of C. difficile and could be used to reduce the high incidence of relapse after vancomycin treatment in humans. ...
... The probiotic yeast Saccharomyces boulardii has been investigated as a potential exogenously administered agent for maintaining colonization resistance during antibiotic therapy. 101 S. boulardii decreased C. difficile associated cecitis and death in hamsters 101,102 and antibiotic associated diarrhea in humans. 103 A hamster model of recurrent C. difficile was described by Elmer et al. 38 The authors suggested that S. boulardii administration may help prevent extensive overgrowth of C. difficile and could be used to reduce the high incidence of relapse after vancomycin treatment in humans. ...
Models of Clostridium difficile infection (C. difficile) have been used extensively for Clostridium difficile (C. difficile) research. The hamster model of C. difficile infection has been most extensively employed for the study of C. difficile and this has been used in many different areas of research, including the induction of C. difficile, the testing of new treatments, population dynamics and characterization of virulence. Investigations using in vitro models for C. difficile introduced the concept of colonization resistance, evaluated the role of antibiotics in C. difficile development, explored population dynamics and have been useful in the evaluation of C. difficile treatments. Experiments using models have major advantages over clinical studies and have been indispensible in furthering C. difficile research. It is important for future study programs to carefully consider the approach to use and therefore be better placed to inform the design and interpretation of clinical studies.
... We modified this procedure to obtain a reproducible animal model of the relapse of PMC that occurs in humans after cessation of vancomycin treatment. This model was used to study the effect of Saccharomyces boulardii, a nonpathogenic yeast which had previously been shown to decrease C. difficileassociated cecitis and death (13,19). We hypothesized that it could decrease the rate of PMC relapse after cessation of vancomycin treatment. ...
... (7,8,15), and (iv) has been shown to decrease antibiotic-associated diarrhea in clinical trials in humans (2,11,18). Previous work (13,19) has demonstrated a decrease in mortality for S. boulardii-treated hamsters given clindamycin (an animal model for human PMC). The present study employed a protocol designed to simulate the relapse frequently observed after vancomycin treatment of human PMC. ...
Saccharomyces boulardii prevented the development of high counts of Clostridium difficile, high titers of toxin B, and positive
latex agglutination tests after cessation of vancomycin treatment for hamsters. The protocol used was designed to stimulate
relapse of human C. difficile-associated colitis. S. boulardii was protective in this model.
... This work using gnotobiotic mice demonstrated the efficiency of preventive S. boulardii treatment against disease due to C. difficile, in agreem ent with previous studies on clindamycin-treated hamsters (Massot et al. 1984;Toothaker and Elmer 1984). Our results showed that the protection did not seem to be related to any antagonistic effect of yeast against C. difficile in the lumen, since the number of C. difficile was not statistically different from that of the control. ...
... The mechanism of protection by S. boulardii in clindamycin-treated hamsters is still unknown (Massot et al. 1984;Toothaker and Elmer 1984). It may be related, as in our model with gnotobiotic mice, to a modulation of cytotoxin production. ...
Oral preventive treatment of gnotobiotic mice by Saccharomyces boulardii significantly decreased mortality following Clostridium difficile infection. A single S. boulardii ingestion protected 16% of mice, whereas 56% were protected when S. boulardii was given continuously in the drinking water. No direct antagonistic effect of the yeast on C. difficile numbers was detected, whereas a modulation of fecal cytotoxin production was demonstrated.
... The use of a Saccharomyces cerevisiaebased ointment for haemorrhoids has been quite diffuse in the proctologist community for several years. One study reported the beneficial effects of S. cerevisiae against Clostridium difficile infections [96]. In another study on pigs, S. cerevisiae was able to reduce the translocation of enterotoxigenic E. coli (ETEC), strengthening mucosal immunity [97]. ...
To date, the exact pathophysiology of haemorrhoids is poorly understood. The different philosophies on haemorrhoids aetiology may lead to different approaches of treatment. A pathogenic theory involving a correlation between altered anal canal microflora, local inflammation, and muscular dyssynergia is proposed through an extensive review of the literature. Since the middle of the twentieth century, three main theories exist: (1) the varicose vein theory, (2) the vascular hyperplasia theory, and (3) the concept of a sliding anal lining. These phenomena determine changes in the connective tissue (linked to inflammation), including loss of organization, muscular hypertrophy, fragmentation of the anal subepithelial muscle and the elastin component, and vascular changes, including abnormal venous dilatation and vascular thrombosis. Recent studies have reported a possible involvement of gut microbiota in gut motility alteration. Furthermore, dysbiosis seems to represent the leading cause of bowel mucosa inflammation in any intestinal district. The alteration of the gut microbioma in the anorectal district could be responsible for haemorrhoids and other anorectal disorders. A deeper knowledge of the gut microbiota in anorectal disorders lays the basis for unveiling the roles of these various gut microbiota components in anorectal disorder pathogenesis and being conductive to instructing future therapeutics. The therapeutic strategy of antibiotics, prebiotics, probiotics, and fecal microbiota transplantation will benefit the effective application of precision microbiome manipulation in anorectal disorders.
... In a study evaluating the beneficial effects of fungi, S. cerevisiae (baker's yeast), a commonly studied fungi, was used as a probiotic to prophylactically prevent Clostridium difficile infections (Massot et al., 1984). In another porcine study, S. cerevisiae was able to reduce the translocation of enterotoxigenic E. coli (ETEC) to confer mucosal immunity (Lessard et al., 2009). ...
The influence of microbiological species has gained increased visibility and traction in the medical domain with major revelations about the role of bacteria on symbiosis and dysbiosis. A large reason for these revelations can be attributed to advances in deep-sequencing technologies. However, the research on the role of fungi has lagged. With the continued utilization of sequencing technologies in conjunction with traditional culture assays, we have the opportunity to shed light on the complex interplay between the bacteriome and the mycobiome as they relate to human health. In this review, we aim to offer a comprehensive overview of the human mycobiome in healthy and diseased states in a systematic way. The authors hope that the reader will utilize this review as a scaffolding to formulate their understanding of the mycobiome and pursue further research.
... A close relative, the yeast S. boulardii, is already used as a commercially available probiotic (Kelesidis and Pothoulakis 2012). As already demonstrated for the first time in the 1980s in animal and human experiments, its major benefits seem to be the reduction of Clostridium difficile growth (Massot et al. 1984) and positive effects on the intestinal immune system (Corthier et al. 1986). ...
The human microbiota consists of bacteria, archaea, viruses, and fungi that build a highly complex network of interactions between each other and the host. While there are many examples for commensal bacterial influence on host health and immune modulation, little is known about the role of commensal fungi inside the gut community. Up until now, fungal research was concentrating on opportunistic diseases caused by fungal species, leaving the possible role of fungi as part of the microbiota largely unclear. Interestingly, fungal and bacterial abundance in the gut appear to be negatively correlated and disruption of the bacterial microbiota is a prerequisite for fungal overgrowth. The mechanisms behind bacterial colonization resistance are likely diverse, including direct antagonism as well as bacterial stimulation of host defense mechanisms. In this work, we will review the current knowledge of the development of the intestinal bacterial and fungal community, the influence of the microbiota on human health and disease, and the role of the opportunistic yeast C. albicans. We will furthermore discuss the possible benefits of commensal fungal colonization. Finally, we will summarize the recent findings on bacterial-fungal interactions.
... Bacillus coagulans снижал экспрессию ЦОГ-2 в толстой кишке мышей с колитом, вызванным Clostridium difficile [46]. Следует отметить, что в экспериментальных исследованиях на моделях колита, вызванного C. difficile у животных, была доказана эффективность и других пробиотиков: Saccharomyces boulardii у хомячков [47,48], Saccharomyces boulardii у мышей [49], Saccharomyces cerevisiae 905 у мышей [50], Lactobacillus rhamnosus у хомячков [51], Lactobacillus acidophilus у мышей [52] и Bacillus coagulans GBI-30, 6086 у мышей. Однако в обзоре ведущего специалиста в этой области (FitzpatrickL.R., 2013) указывается на то, что наилучшие результаты дает Bacillus coagulans, поскольку он оказывает действие и на начальную стадию колита, и на процесс выздоровления после введения ванкомицина. ...
Bacillus coagulans has an advantage over most other
bacteria used as probiotics. It occupies an intermediate
position between the genera Bacillusand Lactobacillus, is
a spore-forming bacteria that produce lactic acid.This
bacteria in the spores form can tolerate well technology
processes, resistant to antibiotics and antiseptics, does not
collapse under the influence of gastric juice and bile.
Getting into the duodenum, the spores germinate into
vegetative forms and begin vegetation and growth,
providing probiotic effects.Bacillus coagulansrefers to
semi-residental bacteria - performing in the human probiotic
function, it passes the sporulation phase and slowly
leaves the body, standing out in the faeces in the spores
form. Thus, it does not violate the personal composition
of intestinal microflora.Probiotic Bacillus coagulans
enhances the microbiological composition of the intestine,
increasing the number of obligate microorganisms and
displacing pathogenic flora. Mechanisms of this action
based on the lactic acid production and some bacteriocins
synthesis, also on the immunomodulatory effect - stimulation
of cellular and humoral immunity. The bacterial cell
wall and spores are the main immunomodulatory compounds
of the Bacillus coagulans.Apparently, namely
Bacillus coagulans immunomodulatory properties play a
crucial role in the pharmacological effects. It is now well
known about the important role of immune system in the
pathogenesis of many diseases; it has the clinical effect
without the need for intensive growth of bacteria and
intestinal colonization; even small amounts of spores are
sufficient for pharmacological effect; many experimental
evidences of the spore penetration into the lymphatic
system and interaction with immunocompetent cells, as
well as local and systemic immune effects of probiotic.In
addition to this main action, Bacillus coagulans helps to
digest lactose, possesses anti-inflammatory and antioxidant
activity, as well as the cholesterol-lowering effect.
The effectiveness of probiotics, containing spores of
Bacillus coagulans, was confirmed by evidence-based
medicine. Probiotic effect in the treatment of various
diarrheas, including those related to antibiotic treatment,
enterocolitis and irritable bowel syndrome. Bacillus coagulans
application reduces the duration of diarrhea,
reduces the severity of abdominal pain, and normalizes
the composition of intestinal microflora.Bacillus coagulans
efficiency is identified also as hypocholesterolemic
agents, as a means of anti-inflammatory effect in the
combination therapy of arthritis, in combination with soya
extracts for reducing menopause symptoms; by topical
application it was effective in vaginitis, stomatitis and
dental caries. In clinical studies proved the high safety of
probiotics. Except spores Bacillus coagulans, as part of
the “Laktovit Forte” there are also present B9 and B12
vitamins in high doses, which are an essential component
for the early spore’s vegetation in the large intestine.
These vitamins stimulation phenomenon vegetation dispute
has been confirmed experimentally, as shown in the
clinic acceleration by 1-2 days of initial clinical manifestations
of the effects of Bacillus coagulans, which is quite
critical in acute diarrhea microbial origin, abdominal pain
and cramps.
... Later studies made possible the administration of Saccharomyces yeast in the treatment of B avitaminosis, colitis, acute diarrhea and diabetes (Hochter, 1990;Offenbacher et al., 1985;Massot et al., 1984) due to its high content in the vitamins B group. The viable yeast biomass is also used as an additional source for proteins and vitamins in malnutrition and denutrition cases (Segal, 1991). ...
A mutant strain of the yeast Saccharomyces cerevisiae growing on ethanol as single source of carbon and energy was used in optimization experiments at laboratory and micropilot scale, following the surface response methodology. The cultivation medium optimization was performed on the basis of maximization of dry cell weight and the process parameters optimization on the basis of substrate yield maximization.
... Animal studies have indicated that S . boulardii protects both hamsters and gnotobiotic mice from C. difficile infec-tion (Toothaker, 1984;Massot et al., 1984;Castex et al., 1990). For example, Corthier and co-workers (1986) found that a single dose of S. boulardii protected 16% of gnotobiotic mice from C. difficile infection, whereas 56% were protected when S. boulardii was given continuously in the drinking water. ...
... Table 1 shows a list of some probiotics that were tested in pre-clinical models of C. difficile-induced colitis. Early studies, which were conducted approximately 30 years ago, showed that Saccharomyces boulardii could prevent Clindamycin (and by association C. difficile)-induced mortality in hamsters, with improvement in the histological appearance of the intestine in these animals [40,41] . In the same time period, Corthier et al [42] found that Saccharomyces boulardii could limit mortality in gnotobiotic mice that were infected with C. difficile. ...
The purpose of this review paper is to update the current and potential future role of probiotics for Clostridium difficile-associated disease (CDAD). Included in this review, is an update on the testing of newer probiotics (e.g., Bacillus coagulans GBI-30, 6086) in animal models of CDAD. There is a focus on the modulation of signal transduction pathways (i.e., transcription factors like cAMP response element-binding, activator protein 1, and nuclear factor kappa B), as well as the inhibition of certain kinases (e.g., p38 mitogen activated protein kinases) by probiotics. Inhibition of signal transduction by probiotics, such as Saccharomyces boulardii, result in multiple effects on intestinal fluid secretion, neutrophil influx into the colon, inflammation, and colonocyte apoptosis that may positively impact CDAD. Recent clinical approaches with probiotics, for the prevention of primary and recurrent CDAD, are also summarized in this review paper. Future directions for the treatment of CDAD by probiotics are also mentioned in this review. In particular, the use of multi-strain probiotic formulations such as Ecologic(®) AAD and VSL #3(®) may represent a rationale pharmacological approach, particularly as adjunctive therapies for CDAD. Understanding the mechanistic basis of CDAD, and how probiotics interfere at ceratin steps in the pathogenic process, may also present the opportunity to design other multi-strain probiotics that could have a future impact on CDAD.
... In 1899 Brocq was the first scientist who studied the action of the yeast S. cerevisiae in the cutaneous diseases, starting from the observation that the workers from the beer plants were not affected by furunculosis. Later studies made possible the administration of Saccharomyces yeast in the treatment of B avitaminosis, colitis, acute diarrhea and diabetes (Hochter, 1990; Offenbacher et al., 1985; Massot et al., 1984) due to its high content in the vitamins B group. The viable yeast biomass is also used as an additional source for proteins and vitamins in malnutrition and denutrition cases (Segal, 1991). ...
A mutant strain of the yeast Saccharomyces cerevisiae growing on ethanol as single source of carbon and energy was used in optimization experiments at laboratory and micropilot scale, following the surface response methodology. The cultivation medium optimization was performed on the basis of maximization of dry cell weight and the process parameters optimization on the basis of substrate yield maximization.
... This has also been used successfully in hamsters and is now being tried in human patients. The yeast Saccharomyces boulardii has been used successfully to protect hamsters from clindamycin-associated enterocolitis and relapse following vancomycin treatment (64,154,232), but clinical trials in PMC patients have not been reported. ...
Clostridium difficile is the etiologic agent of pseudomembranous colitis, a severe, sometimes fatal disease that occurs in adults undergoing antimicrobial therapy. The disease, ironically, has been most effectively treated with antibiotics, although some of the newer methods of treatment such as the replacement of the bowel flora may prove more beneficial for patients who continue to relapse with pseudomembranous colitis. The organism produces two potent exotoxins designated toxin A and toxin B. Toxin A is an enterotoxin believed to be responsible for the diarrhea and mucosal tissue damage which occur during the disease. Toxin B is an extremely potent cytotoxin, but its role in the disease has not been as well studied. There appears to be a cascade of events which result in the expression of the activity of these toxins, and these events, ranging from the recognition of a trisaccharide receptor by toxin A to the synergistic action of the toxins and their possible dissemination in the body, are discussed in this review. The advantages and disadvantages of the various assays, including tissue culture assay, enzyme immunoassay, and latex agglutination, currently used in the clinical diagnosis of the disease also are discussed.
... Focus has been given recently in the application of S. boulardii in C. difficile-associated diarrhea and colitis. Animal studies indicated that S. boulardii protected hamsters and gnotobiotic mice from C. difficile colitis (15)(16)(17)(18)(19). In a prospective double-blind controlled study, Surawicz et al. reported that 31% of C. difficile-positive patients on placebo developed diarrhea compared with 9.4% on S. boulardii (20). ...
Saccharomyces boulardii is a nonpathogenic yeast used for the prevention and treatment of Clostridium difficile-associated diarrhea and colitis. However, the mechanism by which S. boulardii exerts its protective effects remains unclear.
The binding of [3H]toxin A to its brush border receptor preincubated with S. boulardii-cultured suspension or filtered conditioned medium was measured in vitro. The effect of toxin A on secretion, epithelial permeability, and morphology in rat ileal loops in vivo was also examined in rats pretreated with S. boulardii.
S. boulardii reduced [3H]toxin A-receptor binding in a dose-dependent fashion. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of ileal brush border exposed to S. boulardii-conditioned medium revealed a diminution of all brush border proteins. Treatment of rats with S. boulardii suspension reduced fluid secretion and mannitol permeability caused by toxin A.
S. boulardii may reduce some of the enterotoxic effects of toxin A by inhibiting toxin A-receptor binding. This effect appears to be manifested by a secreted product of the yeast, possibly a protease.
... Buts et al. (5) reported rapid symptomatic and bacteriologic recovery in 16 of 19 children treated with S. boulardii for acute C. difficile infection. S. boulardii treatment also protected animals from the effects of either toxigenic C. difficile or purified toxin A administration (8,9,13,19,26,33). ...
Saccharomyces boulardii, a nonpathogenic yeast, is effective in treating some patients with Clostridium difficile diarrhea and colitis. We have previously reported that S. boulardii inhibits rat ileal secretion in response to C. difficile toxin A possibly by releasing a protease that digests the intestinal receptor for this toxin (C. Pothoulakis, C. P. Kelly, M. A. Joshi, N. Gao, C. J. O'Keane, I. Castagliuolo, and J. T. LaMont, Gastroenterology 104: 1108-1115, 1993). The aim of this study was to purify and characterize this protease. S. boulardii protease was partially purified by gel filtration on Sephadex G-50 and octyl-Sepharose. The effect of S. boulardii protease on rat ileal secretion, epithelial permeability, and morphology in response to toxin A was examined in rat ileal loops in vivo. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified S. boulardii protease revealed a major band at 54 kDa. Pretreatment of rat ileal brush border (BB) membranes with partially purified protease reduced specific toxin A receptor binding (by 26%). Partially purified protease digested the toxin A molecule and significantly reduced its binding to BB membranes in vitro (by 42%). Preincubation of toxin A with S. boulardii protease inhibited ileal secretion (46% inhibition, P < 0.01), mannitol permeability (74% inhibition, P < 0.01), and histologic damage caused by toxin A. Thus, S. boulardii protease inhibits the intestinal effects of C. difficile toxin A by proteolysis of the toxin and inhibition of toxin A binding to its BB receptor. Our results may be relevant to the mechanism by which S. boulardii exerts its protective effects in C. difficile infection in humans.
... In vitro, it has been demonstrated that the protease of 54 kDa digests both toxin A and the receptor on the enterocyte [28]. In vivo, Saccharomyces boulardii decreases the mortality rate, the quantity of toxin A and the intestinal lesions caused by Clostridium d@cile [29,30]. ...
Intestinal barrier defects lead to “leaky gut syndrome”, defined as an increase in intestinal permeability that allows the passage of luminal content into intestinal tissue and the bloodstream. Such a compromised intestinal barrier is the main factor underlying the pathogenesis of inflammatory bowel disease, but also commonly occurs in various systemic diseases such as viral infections and metabolic syndrome. The non-pathogenic yeast Saccharomyces boulardii CNCM I-745 has demonstrated its effectiveness as a probiotic in the prevention and treatment of antibiotic-associated, infectious and functional diarrhea. Via multiple mechanisms of action implicated in intestinal barrier function, S. boulardii has beneficial effects on altered intestinal microbiota and epithelial barrier defects in different pathologies. The well-studied probiotic yeast S. boulardii plays a crucial role in the preservation and/or restoration of intestinal barrier function in multiple disorders. This could be of major interest in diseases characterized by alterations in intestinal barrier function.
Appetit ist ein komplexes psychosomatisches Verlangen nach Nahrungsaufnahme allgemein oder nach einer ganz bestimmten Speise (Thiele 1982). Appetitmangel kann Begleiterscheinung von Krankheiten (Infektionskrankheiten, Magen-Darm-Erkrankungen, Maligno-me) sein, er kann psychosomatischer Natur sein (Anorexia nervosa, emotionale Störungen), er kann medikamentös bedingt sein (Zytostatika, indirekte Sympathomimetika).
Clostridium difficile is the most frequent cause of antibiotic-associated diarrhea and colitis in hospitals. Although the illness generally responds well to treatment with oral vancomycin or metronidazole, approximately 20% of patients experience a recurrence within 6-8 weeks after the discontinuation of specific antibiotic therapy. Some unfortunate patients experience repeated episodes over a period of 6-12 months or more, and until recently there has been no scientifically proven way to terminate this syndrome, which is thought to be caused by poorly understood antibiotic-induced aberrations in the ecology of the fecal flora that normally inhibits the growth and toxin production of C. difficile. Saccharomyces boulardii ( Sb), a yeast which is found naturally on some fruits, was reported in two studies to effectively prevent antibiotic associated diarrhea and was thus investigated as an effective treatment for C. difficile disease. A multicenter randomized placebo controlled trial of S. boulardii in prevention of recurrent CDAD was conducted at the Universities of Washington, Kentucky and Michigan, and the results were reported in 1994. It was designed to determine the efficacy of orally administered S. boulardii (two 250 mg capsules twice per day containing 3 x 1010 CFU/day of Sb) in prevention of a recurrence of CDAD in patients with either their first or a recurrent episode of Clostridium difficile diarrhea or colitis. Immunosuppressed patients were excluded from the study. Each of 124 participants was treated with either vancomycin or metronidazole, and then with Sb or a placebo as well, for at least the last four days of antibiotic therapy, after which Sb or placebo was continued for a total of four weeks. Patients were followed for an additional four weeks and suspect recurrences were confirmed by stool cultures and toxin tests. Among 64 patients with their first episode of CDAD, the rate of recurrence was 19.3% in patients receiving Sb and 24.2% with placebo (NSS). In 60 patients with recurrent CDAD, the rate of another recurrence was significantly lower with Sb (9 of 26, 34.6%) than it was among placebo recipients (22 of 34, 64.7%) (p = 0.04). The rates of recurrence were not related to whether vancomyin or metronidazole was used in treatment. There were no side effects of the use of Sb other than thirst and constipation.
In summary, Saccharomyces boulardii was found to be safe and significantly more effective than placebo in prevention of C. difficile associated diarrhea or colitis. The ability of S. boulardii to prevent CDAD in patients suffering from recurrent episodes is particulary interesting, as this is the only therapy that has been shown in a wellcontrolled study to be effective in terminating this troublesome syndrome. Sb is not pathogenic, it is not a component of the normal fecal flora, and it does not permanently colonize the colon. As yet, all the mechanism(s) of the protective effect of Sb have not been established. Further studies of Sb with different types of patients with C. difficile diarrheal syndromes are underway.
Saccharomyces boulardii is a non-pathogenic yeast effectively used in the prevention and treatment of Clostridium difficile-mediated diarrhea and colitis. Several putative mechanisms for the protective effects of S. boulardii have been proposed based on results from human as well as animal studies for C. difficile diarrhea and intestinal inflammation. Treatment of humans and rats with S. boulardii increases the intestinal levels of the disaccharidases maltase and lactase. Subsequent studies indicated that polyamines released from S. boulardii itself may cause these trophic effects on the small intestine. Administration of S. boulardii to rats also increases the intestinal levels of the secretory component of immunoglobulins and of secretory IgA, indicating that this yeast may exert an immunoprotective effect against C. difficile and its toxins. Pretreatment of animals with S. boulardii protects from death following C. difficile infection and this effect could be mediated by a yeast effect on C. difficile bacterium as well as its toxins A and B. Results from our laboratory showed that treatment of rats with S. boulardii before addition of toxin A to rat intestine substantially reduced the enterotoxic effects of toxin A. Further experiments indicated that these effects of S. boulardii are mediated, at least in part, by a yeast secreted protease which is able to digest toxin A as well as its intestinal receptor in vitro. These results suggest that S. boulardii reduces the intestinal effects of C. difficile toxin A by digesting the toxin A molecule as well as its intestinal brush border receptor.
Taken together, results from our as well as other laboratories provide several possible mechanisms for the action of S. boulardii on human C. difficile infection. These include: (1) proteolysis of toxin A and its intestinal receptor by a yeast protease, (2) a direct inhibition of C. difficile growth, (3) enhancement of an intestinal immune response and (4) stimulation of intestinal disaccharidase activity possibly through release of polyamines by S. boulardii.
Pseudomembranous colitis and a large percentage (about 30%) of antibiotic-associated diarrhoea are caused by the overgrowth of Clostridium difficile in the human digestive tract. This overgrowth is mainly due to disorders in gut bacterial populations leading to disruption of the colonization resistance to pathogens (Hentges, 1992). C. difficile produces two toxins (an enterotoxin and a cytotoxin) which are responsible for the disease (Figure 3.1). Medical treatments mostly involve antibiotics (vancomycin or metronidazole) that do not facilitate the restoration of the colonization resistance, so that relapses are often observed. The aim of this chapter is to overview C. difficile-associated enteropathies as well as bacterial toxins and to present the current and future applications of probiotic treatments in a preventive or curative mode.
Clostridium difficile is the most frequent cause of antibiotic-associated diarrhea and colitis in hospitals. Although the illness generally responds well to treatment with oral vancomycin or metronidazole, approximately 20% of patients experience a recurrence within 6–8 weeks after the discontinuation of specific antibiotic therapy. Some unfortunate patients experience repeated episodes over a period of 6–12 months or more, and until recently there has been no scientifically proven way to terminate this syndrome, which is thought to be caused by poorly understood antibiotic-induced aberrations in the ecology of the fecal flora that normally inhibits the growth and toxin production of C. difficile. Saccharomyces boulardii (Sb), a yeast which is found naturally on some fruits, was reported in two studies to effectively prevent antibiotic associated diarrhea and was thus investigated as an effective treatment for C. difficile disease. A multicenter randomized placebo controlled trial of S. boulardii in prevention of recurrent CDAD was conducted at the Universities of Washington, Kentucky and Michigan, and the results were reported in 1994. It was designed to determine the efficacy of orally administered S. boulardii (two 250 mg capsules twice per day containing 3 × 1010 CFU/day of Sb) in prevention of a recurrence of CDAD in patients with either their first or a recurrent episode of Clostridium difficile diarrhea or colitis. Immunosuppressed patients were excluded from the study. Each of 124 participants was treated with either vancomycin or metronidazole, and then with Sb or a placebo as well, for at least the last four days of antibiotic therapy, after which Sb or placebo was continued for a total of four weeks. Patients were followed for an additional four weeks and suspect recurrences were confirmed by stool cultures and toxin tests. Among 64 patients with their first episode of CDAD, the rate of recurrence was 19.3% in patients receiving Sb and 24.2% with placebo (NSS). In 60 patients with recurrent CDAD, the rate of another recurrence was significantly lower with Sb (9 of 26, 34.6%) than it was among placebo recipients (22 of 34, 64.7%) (p = 0.04). The rates of recurrence were not related to whether vancomyin or metronidazole was used in treatment. There were no side effects of the use of Sb other than thirst and constipation.
In summary, Saccharomyces boulardii was found to be safe and significantly more effective than placebo in prevention of C. difficile associated diarrhea or colitis. The ability of S. boulardii to prevent CDAD in patients suffering from recurrent episodes is particulary interesting, as this is the only therapy that has been shown in a well-controlled study to be effective in terminating this troublesome syndrome. Sb is not pathogenic, it is not a component of the normal fecal flora, and it does not permanently colonize the colon. As yet, all the mechanism(s) of the protective effect of Sb have not been established. Further studies of Sb with different types of patients with C. difficile diarrheal syndromes are underway.
Saccharomyces boulardii is a non-pathogenic yeast effectively used in the prevention and treatment of Clostridium difficile-mediated diarrhea and colitis. Several putative mechanisms for the protective effects of S. boulardii have been proposed based on results from human as well as animal studies for C. difficile diarrhea and intestinal inflammation. Treatment of humans and rats with S. boulardii increases the intestinal levels of the disaccharidases maltase and lactase. Subsequent studies indicated that polyamines released from S. boulardii itself may cause these trophic effects on the small intestine. Administration of S. boulardii to rats also increases the intestinal levels of the secretory component of immunoglobulins and of secretory IgA, indicating that this yeast may exert an immunoprotective effect against C. difficile and its toxins. Pretreatment of animals with S. boulardii protects from death following C. difficile infection and this effect could be mediated by a yeast effect on C. difficile bacterium as well as its toxins A and B. Results from our laboratory showed that treatment of rats with S. boulardii before addition of toxin A to fat intestine substantially reduced the enterotoxic effects of toxin A. Further experiments indicated that these effects of S. boulardii are mediated, at least in part, by a yeast secreted protease which is able to digest toxin A as well as its intestinal receptor in vitro. These results suggest that S. boulardii reduces the intestinal effects of C. difficile toxin A by digesting the toxin A molecule as well as its intestinal brush border receptor.
Taken together, results from our as well as other laboratories provide several possible mechanisms for the action of S. boulardii on human C. difficile infection. These include: (1) proteolysis of toxin A and its intestinal receptor by a yeast protease, (2) a direct inhibition of C. difficile growth, (3) enhancement of an intestinal immune response and (4) stimulation of intestinal disaccharidase activity possibly through release of polyamines by S. boulardii.
Mikroorganismenpräparate, die lebende oder lebensfähige Keime enthalten, werden Scit vielen Jahren zur Prophylaxe und Therapie von Durchfallerkrankungen eingesetzt. Als Hypothese zum Wirkungsmechanismus wird in erster Linie eine Beeinflussung des intestinalen mikrobiellen Gleichgewichts, das beim Menschen von ca. 400 verschiedenen Bakterienarten bei einer Gesamtkeimzahl von etwa 1014 gebildet wird [12], diskutiert. Hauptaugenmerk wird dabei auf die Konkurrenz zu Krankheitserregern gerichtet, die über die Ausscheidung antibiotikaähnlicher Substanzen, die Konkurrenz um Adhäsionsstellen oder einfache Nährstoffkonkurrenz vermittelt werden soll [11,21].
Diarrhöen zählen mit einer Inzidenz von ca. 20 % [17, 33] neben den allergischen Hautreaktionen zu den häufigsten Nebenwirkungen der Antibiotika. Das klinische Spektrum der antibiotikaassoziierten Diarrhö reicht von einer passageren leichten Erhöhung der Stuhlfrequenz bis hin zur pseudomembranösen Kolitis (antibiotikaassoziierte Kolitis), die in seltenen Fällen einen letalen Verlauf nehmen kann.
Antibiotic associated diarrhea is one of the most frequent adverse effects of antimicrobial agents. Although usually self limiting upon termination of the antibiotic, it may not always be feasible to stop antibiotherapy. For some patients, diarrhea may exacerbate an already serious condition by dehydration and/or by perturbation to the electrolyte balance. Most antibiotic associated diarrhea is thought to be due to an imbalance in the intestinal flora created by destruction or suppression of those components of the intestinal flora that exhibit a barrier effect against the overgrowth of diarrhea causing pathogens [21, 22]. Increases in unabsorbed carbohydrates or altered fatty acids in the gut may also play roles in the etiology [17, 18].
A double-blind placebo-controlled study was designed to evaluate the efficacy and tolerability of the yeast Saccharomyces boulardii as an antidiarrheal agent in 100 infant and small children with acute diarhoreal illness. Evaluation of the results showed reduction in the number of stools and an improvement in their consistency in Saccharomyces boulardii group. After 48h and 96h children treated with Saccharomyces boulardii scored better than controls. It is concluded that in Saccharomyces boulardii group significantly more children recovered and normalised stolls than controls without adverse reactions. This yeast can be used as an adjunct to oral rehydration in treating acute diarrhea in infants.
Clostridium difficile-associated disease is a classic example of the type of disease that may be most amenable to treatment with biotherapeutic agents (BTA). The gastrointestinal tract contains a complex milieu of interacting organisms whose populations may shift dramatically in response to antibiotics, medications, or medical procedures. The most common result of the disruption of colonic equilibrium is diarrhea. Opportunistic pathogens may establish a disease state when the host’s normal microbiologic flora has been disturbed, and although most cases may respond at first to antimicrobial therapy, a permanent cure relies on the re-establishment of the normal flora. Additional antibiotic treatment may actually be detrimental in that the continual disruption by different types of antibiotics slows the recovery of normal flora. In these types of diseases, BTA may prove to be most beneficial.
The probiotics Saccharomyces boulardii and Bacillus cereus var. toyoi are nonpathogenic microbes which have been shown to affect certain functions of the mucosal barrier in pig jejunum such as electrogenic ion transport capacity and paracellular permeability. The present studies were performed to investigate potential effects of the probiotics on jejunal nutrient transport such as sodium-dependent glucose transport or proton-dependent dipeptide transport. For this purpose the in vitro Ussing-chamber technique was applied in order to examine net electrogenic ion flux rates (short circuit currents, Isc) across isolated intact jejunal epithelia in the absence and presence of either 10 mmol/l glucose (mucosal side) or two-fold application of 5 mmol/l glycyl- l-sarcosine or glycyl- l-glutamine to the mucosal bathing solution. Brush border membrane vesicles (BBMV) were prepared in order to characterize kinetic parameters (Vmax, Km) of Na-dependent glucose transport. Intestinal tissues were obtained from growing pigs in a weight range between 23 and 33 kg. All animals were fed twice daily and received 0.8–0.9 kg/day of a standard diet. After a 9- to 10-day adaptation period the diets for treated animals were either supplemented for 8 days with 1.7×107 colony-forming units (CFU)/g feed of S. boulardii or for 3 weeks with 106 CFU/g feed B. cereus var. toyoi. Under basal conditions Isc values were not affected by different treatment protocols (controls: 0.74 ± 0.04 µeq/cm2 per h, n=9; S. boulardii: 0.74 ± 0.12 µeq/cm2 per h, n=7; B. cereus 0.68 ± 0.09 µeq/cm2 per h, n=5). Irrespective of dietary treatment, the addition of glucose resulted in significant increases of Isc indicating substantial onset of electrogenic net Na/glucose cotransport. Maximal Isc values occurred within 30 min and reached 2.79 ± 0.41 µeq/cm2 per h in control epithelia. This was significantly lower than found in S. boulardii (4.47 ± 0.43 µeq/cm2 per h, p < 0.05) and B. cereus var. toyoi tissues (4.45 ± 0.31 µeq/cm2 per h, p < 0.05). Gt values were 22.4 ± 1.3 mS/cm2 in control animals and were significantly lower as shown in S. boulardii (p < 0.01) and B. cereus var. toyoi (p < 0.01)-treated animals (28.4 ± 1.3 and 29.9 ± 0.8 mS/cm2, respectively). Vmax values of Na-dependent glucose uptake into BBMV differed significantly between controls (0.64 ± 0.08 nmol/mg protein per 10 s; n=5), S. boulardii (0.89 ± 0.06 nmol/mg protein per 10 s; n=5, p < 0.05) and B. cereus var. toyoi preparations (1.08 ± 0.05 nmol/mg protein per 10 s; n=3, p < 0.01). Km values were not significantly affected (control: 0.31 ± 0.04 mmol/l, S. boulardii: 0.29 ± 0.05 mmol/l, B. cereus var. toyoi: 0.21 ± 0.01 mmol/l). Irrespective of dietary treatment, application of the dipeptide model substances glycyl- l-sarcosine or glycyl- l-glutamine resulted in significant increases of Isc indicating marked stimulation of electrogenic net H+/dipeptide cotransport. Highest Isc responses occurred in B. cereus var. toyoi preparations and lowest were found in control tissues. However, these differences were not significant. Gt values were not affected by different dietary treatments. The results clearly demonstrate that oral administration of either S. boulardii or B. cereus var. toyoi stimulates Na-dependent glucose absorption in pig jejunum.
In summary, altered intestinal ecology is very important in the pathogenesis of antibiotic-associated diarrhea and pseudomembranous colitis. Prevention of AAD has been demostrated with LactobacillusGG, Enterococcus SF68, and S. boulardii. While therapy with antibitics such as vancomycin or metranidazole is effective for PMC, relapse can occur and is difficult to treat. Antibiotics can be given, but another approach of restoring the normal colonic ecology may be more effective. Such therapy has included use of the nontoxigenic strains of C. difficile, rectal infusions of homologous feces or mixtures of bacteria, and oral administration of Lactobaccillus GG and the live yeast Saccharomyces boulardii.
Saccharomyces boulardii is a nonpathogenic yeast used in the treatment of Clostridium difficile diarrhea and colitis. We have reported that S. boulardii inhibits C. difficile toxin A enteritis in rats by releasing a 54-kDa protease which digests the toxin A molecule and its brush border membrane (BBM) receptor (I. Castagliuolo, J. T. LaMont, S. T. Nikulasson, and C. Pothoulakis, Infect. Immun. 64:5225–5232, 1996). The aim of this study was to further evaluate the role of S. boulardii protease in preventing C. difficile toxin A enteritis in rat ileum and determine whether it protects human colonic mucosa from C. difficile toxins. A polyclonal rabbit antiserum raised against purified S. boulardii serine protease inhibited by 73% the proteolytic activity present in S. boulardii conditioned medium in vitro. The anti-protease immunoglobulin G (IgG) prevented the action of S. boulardii on toxin A-induced intestinal secretion and mucosal permeability to [3H]mannitol in rat ileal loops, while control rabbit IgG had no effect. The anti-protease IgG also prevented the effects of S. boulardii protease on digestion of toxins A and B and on binding of [3H]toxin A and [3H]toxin B to purified human colonic BBM. Purified S. boulardii protease reversed toxin A- and toxin B-induced inhibition of protein synthesis in human colonic (HT-29) cells. Furthermore, toxin A- and B-induced drops in transepithelial resistance in human colonic mucosa mounted in Ussing chambers were reversed by 60 and 68%, respectively, by preexposing the toxins to S. boulardii protease. We conclude that the protective effects of S. boulardii on C. difficile-induced inflammatory diarrhea in humans are due, at least in part, to proteolytic digestion of toxin A and B molecules by a secreted protease.
Clostridium difficile infection is an increasing burden to the health care system, totaling more than $1 billion/year in the United States. Treatment of patients with C difficile infection with metronidazole or vancomycin reduces morbidity and mortality, although the number of patients that do not respond to metronidazole is increasing. Despite initial response rates of greater than 90%, 15%-30% of patients have a relapse in symptoms after successful initial therapy, usually in the first few weeks after treatment is discontinued. Failure to develop specific antibody response has recently been identified as a critical factor in recurrence. The review discusses the different management strategies for initial and recurrent symptomatic C difficile infections.
Human antibiotic-associated diarrhoea and pseudomembranous colitis are partly due to toxin production by Clostridium difficile. It is now well documented that Saccharomyces boulardii protects against C. difficile induced diseases. In an attempt to understand better the mechanism of this protective effect, the action of S. boulardii on a crude toxin preparation was studied in vitro and in vivo. The results showed that the yeast had no effect on the toxins in vitro but was able to protect mice inoculated with these toxins. Furthermore, the observation by scanning electron microscopy that the mucosa of S. boulardii protected mice was not damaged suggest that the yeast mainly acts on the intestinal mucosa.
The ability of viable and nonviable Saccharomyces boulardii to protect gnotobiotic mice from Clostridium difficile induced mortality was tested. With the exception of irradiated S. boulardii, which retained some activity, only viable yeast protected the mice from lethality. The survival of C. difficile infected mice was dependent on the dose of the yeast provided in the drinking water. Key words: Saccharomyces boulardii, Clostridium difficile, colitis, pseudomembranous colitis, gnotobiotic mice.
Pseudomembranous colitis (pmc) is the most severe form and probably the last stage [35] of a spectrum of acute intestinal diseases due mainly to antibiotic administration and with in situ proliferation of toxigenic Clostridium difficile [7],[19].This pathogen seems also to be responsible for cases of pmc not linked to antibiotherapy [7,42](Table 1).
Saccharomyces boulardii (SB) is a yeast that is used for the prevention and treatment of antibiotic-associated diarrhea and for the treatment of pseudomembranous colitis. Since SB will most commonly be used when the bacterial flora of the gastrointestinal tract have been disrupted by antibiotic treatment, the influence of different antibiotics on the kinetics and recovery of SB in feces was investigated in rats. Following a single oral dose, SB concentrations in feces were measured for periods of 1 to 6 days. Although SB is eliminated exclusively in the feces, less than 3% of the dose is recovered as viable yeast. When rats were treated with neomycin, which is active against gram-negative aerobic bacteria but not against anaerobes, no change was observed in recovery of SB when compared with recovery from untreated rats. Also, there was no change in the rate at which SB concentrations declined in feces. In contrast, treatment with clindamycin and the broad-spectrum antibiotic ampicillin, which are active against anaerobes, produced an increase in the recovery of SB of up to seven times that of controls and slowed the rate of decline of SB concentration in the feces. This antibiotic effect on SB disposition was also found when SB was administered in multiple doses. An eightfold increase in the steady-state output of SB was observed from ampicillin-treated animals. Analysis of the recovery and kinetic data showed that the primary effect of these antibiotics was to reduce the destruction of SB, probably in the cecum and colon.(ABSTRACT TRUNCATED AT 250 WORDS)
The ability of Saccharomyces boulardii to protect mice against intestinal pathology caused by toxinogenic Clostridium difficile was studied. Different regions of the intestine of experimental mice were prepared for observation by scanning electron microscopy or homogenized for C. difficile enumeration and quantification of toxin A by enzyme immunoassay and toxin B by cytotoxicity. The test group was treated for 6 d with an S. boulardii suspension in drinking water and challenged with C. difficule on day 4. The three control groups were: axenic mice, mice treated with only S. boulardii and mice only challenged with C. difficile. The results showed that: (i) 70% of the mice infected by C. difficile survived when treated with S. boulardii; (ii) the C. difficile-induced lesions on the small and large intestinal mucosa were absent or markedly less severe in S. boulardii-treated mice; and (iii) there was no decrease in the number of C. difficile but rather a reduction in the amount of toxins A and B in S. boulardii-treated mice.
A short-term oral administration of live Saccharomyces cerevisiae cells, strain Sillix Hansen DSM 1883, resulted in enhanced resistance of mice toward infections with K. pneumoniae. S. pneumoniae and S. pyogenes A produced by intranasal inoculation. Yeast pre-treatment also increased the efficacy of antibiotic therapy in bacterial infections and of antiviral drugs in viral infections. Yeast treatment of animals stimulated phagocytosis, activated the complement system and induced interferon which are likely to represent the main mechanisms of action whereby pretreatment of mice with live S. cerevisiae cells increases resistance to infection. It is concluded that preventive administration of live Saccharomyces cerevisiae cells should be used for increasing resistance to bacterial infections, in particular of the respiratory tract, or to viral infections, as well as an adjunct to antibiotic and antiviral drug therapy.
Saccharomyces boulardii (S.b.) is largely used in Western European countries for the treatment of acute infectious enteritis and antibiotic-induced gastrointestinal disorders. To study the mechanisms of the protective effect of S.b. against enteral pathogen infection, we assessed the response of the intestinal secretion of secretory IgA (s-IgA) and of the secretory component of immunoglobulins (SC) to oral administration of high doses (0.5 mg/g body weight, three times per day) of S.b. cells in growing rats. S.b. cells (biological activity: 2.8 x 10(9) viable cells/100 mg) were administered daily by gastric intubation to weanling rats from day 14 until day 22 postpartum. Control groups received either 0.9% saline or ovalbumin following the same schedule. Expressed per milligram of cell protein, SC content was significantly increased in crypt cells isolated from the jejunum (48.5% vs saline controls, P less than 0.05) as it was in the duodenal fluid (62.8% vs saline controls, P less than 0.01) of rats treated with S.b. Oral treatment with S.b. had no effect on the secretion of SC by the liver. In the duodenal fluid of rats treated with S.b. cells, the mean concentration of s-IgA was increased by 56.9% (P less than 0.01) over the concentration of s-IgA measured in saline controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Saccharomyces boulardii, a nonpathogenic yeast, has been widely used in Europe to prevent antibiotic-associated diarrhea (AAD). We performed a prospective double-blind controlled study to investigate AAD in hospitalized patients and to evaluate the effect of S. boulardii, a living yeast, given in capsule form concurrently with antibiotics. Over 23 mo, 180 patients completed the study. Of the patients receiving placebo, 22% experienced diarrhea compared with 9.5% of patients receiving S. boulardii (p = 0.038). Risk factors found to be associated with AAD were multiple antibiotic combinations (containing clindamycin, cephalosporins, or trimethoprim-sulfamethoxazole) and tube feeding. Clostridium difficile, an anaerobe found in the stools of most patients with pseudomembranous colitis, was variably associated with AAD. We evaluated the role of C. difficile in AAD in the study population and found no significant association between the presence of C. difficile or cytotoxin with AAD. Approximately 33% of the patients without diarrhea harbored at least one C. difficile-positive stool and nearly 50% of these patients had detectable cytotoxin. Similar values were obtained in patients with diarrhea. Of C. difficile-positive patients, 31% (5/16) on placebo developed diarrhea compared with 9.4% (3/32) on S. boulardii; this difference was not statistically significant (p = 0.07). There were no discernable adverse effects of yeast administration. We conclude that S. boulardii reduces the incidence of antibiotic-associated diarrhea in hospitalized patients.
In previous studies, we showed that diet composition or Saccharomyces boulardii ingestion could protect gnotobiotic mice against lethal Clostridium difficile infection. Using an original method, we detected nontoxinogenic clones from feces of protected mice challenged with a toxinogenic clone of C. difficile. These clones became established at the same level as the toxinogenic one after about 30 days. In these protected mice bearing nontoxinogenic clones, no enterotoxin production could be detected and cytotoxin titers were highly reduced. These nontoxinogenic clones were genetically stable because nontoxinogenic clones and clones that produce intermediate levels of toxins in vivo did not revert to toxin production, even after repeated culture in vitro. Furthermore, the nontoxinogenic clones were shown to arise from a single toxinogenic clone and were identical to that clone in metabolic patterns and antibiotic sensitivity tests. When mice fed a nonprotective diet were challenged with a nontoxinogenic or intermediate clone, they remained healthy and no toxin production could be detected in their feces. Moreover, these mice were protected against further infections with toxinogenic strains of C. difficile, and a strong antagonism between nontoxinogenic and toxinogenic clones was observed.
Saccharomyces boulardii is a nonpathogenic yeast that protects against antibiotic-associated diarrhea and recurrent Clostridium difficile colitis. The administration of C. difficile toxoid A by gavage to S. boulardii-fed BALB/c mice caused a 1.8-fold increase in total small intestinal immunoglobulin A levels (P = 0.003) and a 4.4-fold increase in specific intestinal anti-toxin A levels (P < 0.001). Enhancing host intestinal immune responses may be an important mechanism for S. boulardii-mediated protection against diarrheal illnesses.
Treatment of Clostridium difficile infection with metronidazole or vancomycin is successful in the majority of cases, but relapse occurs in 15% to 20% of patients, and in some the infection can remain chronic for months or years. The use of non-antibiotic therapies for this infection is theoretically attractive, as they would enable the normal colonic microflora to be reconstituted which is a requirement for permanent eradication of this pathogen. Over the past decade a number of non-antibiotic approaches to eliminate or neutralize C. difficile or its toxins have been proposed, including probiotic therapy with non-pathogenic microorganisms and several forms of immunotherapy. These alternative approaches are in their infancy, but initial reports appear to support efficacy against this stubborn infection.
For biotherapeutic agents, there is a lack of information on dose-response relationships and mechanism of action. The present study was designed to address these issues for Saccharomyces boulardii using the rat model of castor oil-induced diarrhea. A single dose of Saccharomyces boulardii at 12 x 10(10) CFU/kg of viable cells given 1 hr before castor oil administration significantly reduced the onset of diarrhea. Repeated ingestion of the yeast, twice daily between 1.2 and 12 x 10(10) CFU/kg for 5 days before castor oil, showed a dose-response relationship. The percentage of rats with diarrhea decreased and a stronger protection was afforded by the repeated treatment. The mechanism of action of Saccharomyces boulardii in this model was investigated with two classes of antagonists, naloxone and L-arginine. The effect of Saccharomyces boulardii was not inhibited by naloxone but was significantly reduced by L-arginine. This last result suggests a novel mechanism of action for Saccharomyces boulardii involving a possible inhibition of nitric oxide production by the yeast.
Orally administered Saccharomyces boulardii (synonym Saccharomyces cerevisiae Hansen CBS 5926) has already been shown to affect relevant functions of the mucosa in pig jejunum such as lowering the secretory response to theophylline or stimulating sodium/glucose cotransport, but knowledge of time-dependent relationship is minimal. In this study we examined the effects of S. boulardii on sodium (Na+) and chloride (Cl−) transport in pig jejunum under nonstimulated (basal) and stimulated (secretory) conditions. For this purpose the conventional Ussing chamber method was used for measuring electrical parameters (short circuit currents, I
sc; tissue conductances, G
T) and electrolyte transport of isolated intact jejunal epithelia in the absence and presence of the secretagogue theophylline (10 mM, serosal side). Time profiles of the mucosa response were assessed by treating animals perorally with S. boulardii for 0 (control), 3, 8, and 16 days. Intestinal tissues were obtained from growing pigs in the weight range between 25 and 40 kg. All animals were fed twice daily and received 1.0–1.6 kg/day of a standard diet avoiding probiotics as food additives. After a 9- to 10-day adaptation period the diets for treated animals were supplemented with approximately 1.8·107 colony forming units (CFU)/g feed of the probiotic. Whereas basal tissue conductances were not affected by treatment duration, basal I
sc values decreased significantly during 8 days of treatment, by 26%, indicating a lower electrogenic net ion transport, which, however, was reconstituted after 16 days. This effect could be explained by almost the same reduction of basal J
ms of Na+ during 8 days of treatment, whereas respective flux rates in the opposite direction remained stable. Under basal conditions unidirectional and net flux rates of Cl− were not affected by S. boulardii. Induction of secretory conditions by theophylline revealed pronounced increases in net Cl− secretion but this effect was more than 60% lower after 8-day S. boulardii application, and this was reflected by a respectively lower I
sc stimulation. Interestingly, this inhibitory effect on the secretory response could no longer be observed in the 16-day group. And this was reflected by a respectively lower I
sc stimulation. A similar effect could be observed regarding net Na+ flux rates. Residual fluxes were affected neither by S. boulardii nor by theophylline, therefore, I
sc values can be explained completely by respective Na+ and Cl− fluxes. In conclusion, S. boulardii has specific duration-dependent effects on the secretory response of the pig jejunal mucosa which developed during 8-day treatment but disappeared during further application. Thus, this study supports the concept that probiotics may exert beneficial effects in the gastrointestinal tract.
The biotherapeutic agent Saccharomyces boulardii has been shown to inhibit castor oil-induced diarrhoea in rats in a dose-response fashion, and one of the suggested mechanisms of action included involvement of the nitric oxide pathway. The present study was designed to address this mechanism of action by firstly measuring the effects of S. boulardii on the inducible nitric oxide synthase (iNOS) isoform activity in vitro. Second, the effects of S. boulardii on the increase in colonic citrulline level associated with castor oil treatment were examined. In vitro, S. boulardii showed a dose-dependent inhibition of iNOS activity with an IC50 of 0.89 mg/ml. In the rat diarrhoea model, the antidiarrhoeal effect of S. boulardii was confirmed using a single oral dose of 12 x 10(10) CFU/kg (viable cells). In this model, castor oil significantly elevated citrulline level from 2526+/-164 to 3501+/-193 nmol/g in the colon. When the rats were treated with the same antidiarrhoeal single dose of S. boulardii, no increase in citrulline level was observed. Moreover, the iNOS inhibitor 1400 W at 10 mg/kg and the inhibitor of iNOS expression dexamethasone at 1 mg/kg, administered subcutaneously, blocked the citrulline production induced by the laxative. Taken together, these findings confirm the involvement of inhibition of the inducible isoform of nitric oxide synthase in the mechanism of action of S. boulardii in diarrhoea.
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