Probiotics under the regulatory microscope

This review examines current knowledge regarding the safety of probiotic bacteria in man. Tighter and more comprehensive standards and regulations will be developed as probiotic therapy moves from a limited number of products used in the food industry, into more defined therapeutic categories and more complex organisms. A new framework considering probiotics as nonspecific promoters of mucosal immunity, defines probiotic characteristics and the clinical circumstances in which it is used. For example, those with immune deficiency taking a high dose of viable bacteria may have an increased risk. A wider range of bacteria is now being used, sometimes in territories other than the gut mucosa. The question of competition with multiple isolates must be addressed, as does the use of nonselected faecal isolates. Transfer of antibiotic resistance with probiotics acting as a 'shuttle' needs clarification. These issues are addressed and reviewed as probiotics evolve into a new therapeutic arena.     

Probiotic bacteria: a viable adjuvant therapy for relieving symptoms of rheumatoid arthritis

The burgeoning use of probiotics has proliferated during the past two decades. However, the effect of probiotic administration for either the prevention or treatment of rheumatoid arthritis (RA) has been investigated in a limited number of studies. Randomized controlled clinical trials have provided evidences that specific probiotics supplementation exhibit anti-inflammatory effects, help to increase daily activities and alleviate symptoms in patients with RA. Therefore, using probiotic bacteria as an adjuvant therapy may be considered as a promising treatment option for RA. This review summarizes the available data about the therapeutic and preventive effect of probiotics in RA, together with probiotic supplement as a possible therapy in clinical treatment.     

Genomics can advance the potential for probiotic cultures to improve liver and overall health

The concept of probiotics has evolved immensely since it was first proposed a century ago. There are numerous potential health benefits attributed to certain probiotic bacteria, from preventing gastrointestinal (GI) infections to stimulating the immune system. Recent evidence is now quite compelling for a role of probiotics in enhancing liver health. Liver injury is on the rise worldwide with non-alcohol fatty liver disease (NAFLD) the fastest rising liver problem, due largely to the rise in obesity and type II diabetes. A damaged liver can progress to more serious conditions such as steatohepatitis and cirrhosis, and the intestinal microflora are believed to play a large role in this progression. When the intestinal microbial flora is high in facultative microbes, particularly the Enterobacteriaceae, and low in anaerobes such as bifidobacteria, higher levels of ammonia, endotoxins and other compounds enter the blood stream. This results in direct liver damage and also indirectly from pro-inflammatory cytokines such as TNF-alpha. Probiotics have been shown to modulate the intestinal microflora and decrease the urease producing gram negatives and increase the anaerobic population. While results have been obtained with current probiotic strains, more effective strains could be obtained if all the characteristics bacteria use to survive and compete successfully in the intestine were known. The genomics era is now providing the tools to more effectively understand probiotic interactions in the intestine. This will lead to a new generation of exciting probiotics in the future.     

The place of probiotics in human intestinal infections

A number of studies have been carried out on the effect of several probiotic species on treatment and prevention of intestinal infections. The most commonly used microorganisms are lactic-acid producing bacteria such as lactobacilli and bifidobacteria belonging to the human normal microflora. In vitro and animal studies have shown that probiotic microorganisms interfere with the colonisation of Helicobacter pylori and of enteropathogenic microorganisms. In humans the significance is more uncertain. Clinically significant benefits of probiotics have been demonstrated in the treatment of rotavirus induced diarrhoea and of Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea (AAD). In patients suffering from inflammatory bowel disease, several probiotic strains have been shown to be as effective as traditional medication in preventing relapses. Standardised and well performed studies are needed to elucidate further the mechanisms of action and the clinical significance of probiotics.     

Tetracycline susceptibility of the ingested Lactobacillus acidophilus LaCH-5 and Bifidobacterium animalis subsp. lactis Bb-12 strains during antibiotic/probiotic intervention

We investigated the effects of oral therapy with doxycycline, a tetracycline group antibiotic, on the gastrointestinal (GI) survival and tetracycline susceptibility of probiotic strains Lactobacillus acidophilus LaCH-5 and Bifidobacterium animalis subsp. lactis Bb-12. In addition, the influence of doxycycline therapy on the diversity of the predominant faecal microbiota was evaluated by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE). Faecal samples from the antibiotic group (receiving antibiotics and probiotics) and the control group (receiving probiotics only) were analysed for anaerobically and aerobically growing bacteria, bifidobacteria and lactic acid bacteria as well as for the dominant microbiota. Although doxycycline consumption did not have a large impact on GI survival of the probiotics, it had a detrimental effect on the bifidobacteria and on the diversity of the dominant faecal microbiota. A higher proportion of tetracycline-resistant anaerobically growing bacteria and bifidobacteria was detected in the antibiotic group than in the control group. Several antibiotic group subjects had faecal B. animalis subsp. lactis Bb-12-like isolates with reduced tetracycline susceptibility. This was unlikely to be due to the acquisition of novel tetracycline resistance determinants, since only tet(W), which is also present in the ingested B. animalis subsp. lactis Bb-12, was found in the resistant isolates. Thus, concomitant ingestion of probiotic L. acidophilus LaCH-5 and B. animalis subsp. lactis Bb-12 with the antibiotic did not generate a safety risk regarding the possible GI transfer of tetracycline resistance genes to the ingested strains.     

Probiotics as drugs against human gastrointestinal infections

The commensal gut microbiota confer health benefits to their host by helping dietary digestion, regulating gut immunity, maintaining the microbial balance, and preventing pathogen colonization. A number of probiotic strains have been introduced in the market in dietary and pharmaceutical forms. Lactic acid bacteria (e.g. Lactobacillus) and Bifidobacterium constitute the main group of probiotics commercialized for human consumption. The treatment of gastrointestinal infections continues to be complicated due to the expansion of antibiotic resistances. Of the benefits of probiotics, those related to their preventive and therapeutic uses against gastrointestinal infections have an outstanding position, as reflected in a large number of patents. The mechanisms of action of probiotics against gastrointestinal pathogens addressed in diverse patent applications include: (i) modification of the environmental conditions, (ii) competition for nutrients and adhesion sites, (iii) production of antimicrobial metabolites and (iv) modulation of the immune and non-immune defense mechanisms of the host. The bioactive components of probiotics include cell-wall fractions, surface proteins, nucleic acids, organic and short-chain fatty acids, antimicrobial proteins and other less-well identified soluble factors. The effectiveness of probiotics is supported by solid clinical studies mainly on treatment of acute diarrhea in children and prevention of antibiotic associated disorders. Currently, probiotics and their bioactive compounds constitute attractive alternative drugs that can help to reduce the use of antibiotics as well as to improve conventional pharmacological therapies. The advances on the knowledge of the intricate host-microbe dialogues within the intestine and extraintestinal sites will result in the future development of a new generation probiotic-based products targeting broader range of pathologies and their etiologic agents.     

Probiotics in inflammatory bowel disease--therapeutic rationale and role

The intestinal flora has a conditioning effect on intestinal homeostasis, delivering regulatory signals to the epithelium, the mucosal immune system and to the neuromuscular activity of the gut. Beneficial metabolic activities of the enteric flora include nutrient production, metabolism of dietary carcinogens, conversion of prodrugs to active drugs. However, increasing evidence suggests that some components of the enteric flora are essential ingredients in the pathogenesis of inflammatory bowel disease (IBD); this has prompted interest in therapeutic manipulation of the flora with probiotics. Probiotics are biologic control agents-described as live microbial food supplements which confer a health benefit beyond inherent basic nutrition. Multiple potential beneficial effects have been attributed to the probiotic use of lactic acid bacteria, bifidobacteria and other non-pathogenic commensals. At present, much of the promise of probiotics remains outside the realm of evidence-based medicine and awaits the results of prospective trials, now underway. No reliable in vitro predictors of in vivo efficacy of putative probiotics have been identified. Rigorous comparisons of probiotic performance have not been performed and the suitability of a given probiotic for different individuals is largely unexplored. Notwithstanding, an improved understanding of the normal commensal flora and host-flora interactions has the potential to open up new therapeutic strategies for inflammatory disorders of the gut.     

Review article: yeast as probiotics -- Saccharomyces boulardii

BACKGROUND: Probiotics are defined as live micro-organisms which confer a health benefit on the host. Although most probiotics are bacteria, one strain of yeast, Saccharomyces boulardii, has been found to be an effective probiotic in double-blind clinical studies. AIMS: To compare the main properties that differentiates yeast from bacteria and to review the properties of S. boulardii explaining its potential benefits as a probiotic. METHODS: The PubMed and Medline databases were searched using the keywords 'probiotics', 'yeast', 'antibiotic associated diarrhea', 'Saccharomyces boulardii','bacterial diarrhea' and 'inflammatory bowel disease' in various combinations. RESULTS: Several clinical studies have been conducted with S. boulardii in the treatment and prevention of various forms of diarrhoea. Promising research perspectives have been opened in terms of maintenance treatment of inflammatory bowel diseases. The mechanism of S. boulardii's action has been partially elucidated. CONCLUSION: Saccharomyces boulardii is a strain of yeast which has been extensively studied for its probiotic effects. The clinical activity of S. boulardii is especially relevant to antibiotic-associated diarrhoea and recurrent Clostridium difficile intestinal infections. Experimental studies clearly demonstrate that S. boulardii has specific probiotic properties, and recent data has opened the door for new therapeutic uses of this yeast as an 'immunobiotic'.     

Probiotics and nutraceuticals: non-medicinal treatments of gastrointestinal diseases

The demonstration that immune and epithelial cells can discriminate between different microbial and bioactive plant species has extended the known mechanism(s) of action of nutraceuticals and probiotics beyond simple nutrition and/or antimicrobial effects. The progressive unravelling of these plant and bacterial effects on systemic immune and intestinal epithelial cell function has led to new credence for the use of probiotics and nutraceuticals in clinical medicine. Level I evidence now exists for the therapeutic use of probiotics in infectious diarrhea in children, recurrent Clostridium difficile-induced infections and post-operative pouchitis. Additional evidence is being acquired for the use of probiotics in other gastrointestinal infections, irritable bowel syndrome and inflammatory bowel disease. Not all individual probiotic strains have the same efficacy, and future clinical trials may focus on multistrain preparations agents with known efficacy. The use of nutraceuticals and probiotics as therapeutic agents for gastrointestinal disorders is rapidly moving into clinical usage. Scientific studies are providing mechanisms of action to explain the therapeutic effects, and randomized controlled trials are providing the necessary evidence for their incorporation into the therapeutic armamentarium.     

The role of probiotics in the treatment and prevention of Helicobacter pylori infection

Literature reporting activity of probiotics in infections due to Helicobacter pylori has been reviewed to assess their value in combating such infections. Several in vitro studies show that lactobacilli or their cell-free cultures inhibit or kill H. pylori, prevent its adhesion to mammalian epithelial cells and prevent IL8 release. In vivo models demonstrate that pre-treatment with a probiotic can prevent H. pylori infections and/or that administration of probiotics markedly reduced an existing infection. Thirteen clinical trials have been published. In six (180 patients), a probiotic was used alone; five of these had an encouraging result-in three there were significantly reduced breath test readings and in two others some patients were cleared of infection. In seven further trials (682 patients), probiotics were added to a therapeutic regimen of antibiotics, resulting in an increased cure rate in two studies, and reduced side-effects in four. Trials in which fermented milk products or whole cultures of lactobacilli were used tended to show better results than when the probiotic was taken in the form of bacteria alone. Not all the studies were randomised, double-blind and placebo controlled, and some involved only small numbers of patients. The results suggest that probiotics may have a place as adjunctive treatment in H. pylori infections and possibly in prophylaxis. Future trials should address in particular the type of patient (asymptomatic volunteers, symptomatic patients), choice of probiotic strain(s), a wide range of probiotic strains (Lactobacillus acidophilus, L. johnsonii, L. gasseri, lactobacillus GG, Bifidobacterium longum, and bioyoghurts) have been used-some non-viable, regimens (doses and duration) and criteria of success (breath test, histology, culture, serology).     

Characterization of enterococcus strains contained in probiotic products

Probiotics are additives containing live microbes that beneficially affect a host by improving the properties of the host intestinal microflora. Recently, advances in medical treatments have led to increased numbers of immunocompromised patients; some patients contract opportunistic infections of Enterococcus species, which are considered non-pathogenic bacteria. To evaluate the safety of probiotics containing Enterococcus strains, we isolated Enterococcus from six probiotic products and compared the pathogenic genes and antimicrobial susceptibility of the probiotic strains to those of clinical isolates. Our study showed that all Enterococcus strains contained in probiotic products were E. faecium, and no vancomycin-resistant strains were found. In addition, no pathogenic genes, such as ace, agg, gelE, cylM, cylB, cylA, cpd, cob, ccf, efaA(fs), efaA(fm), esp(fs), or esp(fm), were found in the probiotic strains. Pulsed-field gel electrophoresis (PFGE) analysis showed obvious genetic differences between the probiotic strains and the clinical isolates. The data suggested that the probiotic Enterococcus strains were not transmitted to hospitalized patients. Therefore, our results strongly suggest that probiotic products are unlikely agents for causing opportunistic infections.     

An intimate tête-à-tête - how probiotic lactobacilli communicate with the host

Pharmaceutical agents are routinely used in the treatment of gastrointestinal disorders and their role as modulators of host cell responses is well characterized. In contrast, the understanding of the molecular mechanisms, which determine the role of probiotics, i.e. health-promoting bacteria, as host cell modulators is still in its infancy. Both in vitro and in vivo studies are just starting to reveal the capability of probiotic lactobacilli to modulate host cell-signaling networks and the associated influences on downstream regulatory pathways, including modulation of mucosal cytokine profiles that dictate host immune functions. The communication between probiotic lactobacilli and intestinal host cells is multifactorial and involves an integrative repertoire of receptors on the host side that recognize multiple effector molecules on the bacterial side, of which most have been found to be cell wall- or cell surface-associated compounds and proteins. This review describes the discovery of these bacterial effector molecules and their role in strain- and species-specific modulation of host signaling pathways. Unraveling the mechanisms responsible for probiotic-host interactions will progress this research field towards molecular science and will provide markers for probiotic product quality control as well as host-response efficacy. These developments can ultimately lead to a more dedicated, personalized application of probiotics with strong molecular and scientific support for health promotion.     

细菌基因工程药物研究进展

采用肠道益生菌重构肠道生态平衡,治疗各种代谢相关慢性疾病,是当前保健和医疗行业的热门研究领域。由于人群个体差异,益生菌的治疗效果并不稳定。采用合成生物学手段,将具有特殊治疗作用的功能片段导入益生菌中,创造具有靶向治疗效果的细菌活体药物,对医药发展具有重要影响。本文阐述以各种细菌为治疗载体的活体药物研究进展,包括用于疾病治疗的细菌种类优势、封存技术以及所携带效应物的表达调控。     

Review article: the use of biotherapeutic agents in the prevention and treatment of gastrointestinal disease

There is presently a lack of well conducted clinical trials demonstrating any significant benefits of probiotics in humans. With the exception of diarrhoea due to rotavirus infection in children there is little evidence from randomized, double-blind, placebo-controlled studies that bacterial probiotics have a significant beneficial action in preventing diarrhoea of any cause. The yeast Saccharomyces boulardii has been shown to be of benefit in the prevention of antibiotic-associated diarrhoea but not in preventing infection with Clostridium difficile . S. boulardii may also be of benefit in preventing relapse of C. difficile infection. Because of the simplicity of in vitro systems and some animal models, beneficial characteristics of probiotics such as the ability of bacteria to bind to epithelial surfaces are not always transferable to humans. Thus any postulated benefit from consumption of probiotic bacteria should only be accepted as fact after testing in clinical studies.
This review outlines our present knowledge of the mode of action of probiotics and presents the data from clinical trials on their use.     

Review article: antibiotics and probiotics in inflammatory bowel disease

Treatment with antibiotics in inflammatory bowel disease has a long tradition and is widely used. The indications for antibiotic therapy are wide ranging, from specific situations such as abscesses or fistulae, to patients with severe disease (as an unspecific 'protective' measure), and to address the hypothesis that the enteric flora as a whole, or specific microorganisms such as mycobacteria, are involved in the pathogenesis of inflammatory bowel disease. The best-studied single antibiotic compound is metronidazole. However, overall, the scientific basis for the use of antibiotics is limited, which may reflect a lack of interest from sponsors within the pharmaceutical industry. Despite this weak evidence base, antibiotics are a globally established therapeutic tool in inflammatory bowel disease. Growing evidence from human and animal studies points towards a pivotal pathogenetic role of intestinal bacteria in inflammatory bowel disease. In view of these experimental findings, clinical trials have been undertaken to elucidate the therapeutic effects of probiotics in inflammatory bowel disease. Probiotics are viable nonpathogenic microorganisms which confer health benefits to the host by improving the microbial balance of the indigenous microflora. So far, of the many candidates, one specific strain (Escherichia coli Nissle 1917) and a mixture of eight different bacteria have demonstrated convincing therapeutic efficacy in controlled studies. Maintenance therapy in ulcerative colitis and prevention therapy, as well as the treatment of pouchitis, have emerged as areas in which probiotic therapy offers a valid therapeutic alternative to current treatments. Further investigations may detect additional clinically effective probiotics and other clinical indications.     

Modulation of vaccine response by concomitant probiotic administration

Evidence suggests that probiotic bacteria modulate both innate and adaptive immunity in the host, and in some situations can result in reduced severity of common illnesses, such as acute rotavirus infection and respiratory infections. Responses to vaccination are increasingly being used to provide high quality information on the immunomodulatory effects of dietary components in humans. The present review focuses on the effect of probiotic administration upon vaccination response. The majority of studies investigating the impact of probiotics on responses to vaccination have been conducted in healthy adults, and at best they show modest effects of probiotics on serum or salivary IgA titres. Studies in infants and in elderly subjects are very limited, and it is too early to draw any firm conclusions regarding the potential for probiotics to act as adjuvants in vaccination. Although some studies are comparable in terms of duration of the intervention, age and characteristics of the subjects, most differ in terms of the probiotic selected. Further well designed, randomized, placebo‐controlled studies are needed to understand fully the immunomodulatory properties of probiotics, whether the effects exerted are strain‐dependent and age‐dependent and their clinical relevance in enhancing immune protection following vaccination.     

Probiotics: from functional foods to pharmaceutical products

The concept of probiotics now has been around for more than a century, with its consumption increasing exponentially; owing to exciting scientific and clinical findings, limiting side effects of existing pharmaceutical agents and increased consumer demand for natural products. But, the evidence for their safety and efficacy has largely been anecdotal, lacking an integrated scientific basis. Clinical studies conducted with probiotics were of inadequate design and resulted in unreliable data. That is the reason why despite having innumerable potential therapeutic uses probiotics are not being universally accepted. The purpose of present article is to amalgamate various branches of research which would help in development of "better", "commercial" and "pharmaceutical" probiotic products with defined strength, mechanism of action and indication. Probiotics have been classified into oral and vaginal in accordance to their route of administration, describing the health benefits. The article summarizes the research on significance of strain selection, interactions with co-administered agents and appropriate clinical studies uncovering the safety issues. There is a special emphasis on pharmaceutical issues including probiotic delivery systems, technological challenges during formulation, regulatory concerns, quality control and market potential. Developments in the techniques for in vitro evaluation have also been discussed.     

Survey and Systematic Literature Review of Probiotics Stocked in Academic Medical Centers within the United States

Background:

Probiotics have a wide variation in their effectiveness in preventing or treating conditions due to the varying beneficial effects of specific probiotic strains. In other words, there is no “generic equivalency” between different probiotic species. However, it is has been noted that many practitioners consider probiotics in generic terms and may not realize the impact of these differences between probiotics.

Objective:

The aims of this study were to identify probiotics used in US academic medical centers and to determine whether those probiotics were supported by a reliable evidence base.

Methods:

A phone survey of 126 inpatient pharmacies in US academic medical centers was conducted to determine which probiotics were stocked. A systematic search was conducted to identify relevant studies that were then critically evaluated to determine whether the identified probiotics are supported by a reliable evidence base.

Results:

There was a 90.5% (114/126) response rate of academic medical centers that were contacted through the phone survey. Ten probiotic products were identified through the phone survey. The probiotic most often stocked in academic medical centers was Culturelle (27.2%) followed by Lactinex (25.4%). The systematic search identified evidence that evaluated Culturelle, Florastor, Lactinex, and VSL #3. Of those 4 probiotics, none were supported by a strong evidence base. However, the results suggested that both Culturelle and Florastor appear to be supported by more evidence compared to other probiotics.

Conclusion:

A majority of academic medical centers did not stock a probiotic that was supported by a reliable evidence base.     

Experimental evaluation of subtilact: A new preparation for the treatment of dysbacteriosis

Experimental samples of the new microbiological preparation (probiotic) subtilact ensured the survival of experimental animals with model dysbacteriosis and provide fast normalization of the intestinal microbiocenosis. The combined administration of this probiotic based on B. subtilis 3 and L. plantarum 8P-A3 strains makes it possible to decrease the therapeutic drug dose 1000 times as compared to the well-known probiotics based on bacilli and lactobacilli species. The new probiotic preparation also produces a stimulating effect upon nonspecific immunity parameters, which improves the defensive functions of the organism in experimental animals. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 5, pp. 3–7, May, 2006.     

Probiotics and prebiotics — renaissance of a therapeutic principle

Probiotics are nonpathogenic microorganisms mostly of human origin which, when administered in adequate amounts, confer a health benefit on the host and enable to prevent or improve some diseases. Probiotics may be a natural temporary constituent of the resident intestinal microflora, but their concentration is not sufficient for therapeutic purposes. The microbiota, the intestinal epithelium, and the mucosal immune system constitute the gastrointestinal ecosystem. All three components are essential for complete functional and developmental maturity of the system. The viability of intestinal microflora (including probiotic strains) requires the availability of nutritional substrates (prebiotics), i.e. various types of fiber and oligosaccharides. Prebiotics are cleaved by microbial enzymes to numerous substances (short-chain fatty acids, aminoacids, polyamines, growth factors, vitamins and antioxidants) indispensable for metabolic and functional activities of the intestinal mucosa. The principal probiotics in use include lactobacilli, bifidobacteria, some nonpathogenic strains of Escherichia coli, and Saccharomyces boulardii. These microbiota display favourable effects which qualify them for therapeutic use. For this purpose, probiotics have to fulfill a series of requirements verifying their efficacy and safety. Experimental and clinical studies examine the prerequisites for the administration of probiotics in digestive diseases, allergic and atopic affections, as well as in some extraintestinal conditions. Future goals of probiotic application include genomic analysis, controlled postnatal colonisation of the digestive tract, the use of probiotics as carriers of peroral vaccines, and recombinant probiotics with in-situ production and targeted application of therapeutic molecules.