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Probiotics as a treatment strategy for gastrointestinal diseases?

Current interest in probiotics is motivated not only by the clinical data showing efficacy of some probiotic bacteria but also by the increasing antibiotic resistance of pathogenic bacteria (particularly in hospitals) and the rise of consumers' demand for natural substitutes of drugs. Only few randomized, double-blind placebo-controlled human trials are available, and some involved only small numbers of patients. They are difficult to compare because of differences in probiotic strains employed, doses and formulation. Among probiotic applications, reduction of diarrhea is probably the best-documented effect confirmed by recent meta-analyses. Literature on Helicobacter pylori indicates that probiotics are unable to eradicate the infection but could be useful in decreasing infection levels and as adjuvants of therapy-associated side effects. Studies performed in inflammatory bowel disease suggest that high doses of probiotics and most likely a combination of different lactobacilli and bifidobacteria are more effective in decreasing inflammatory score and maintaining patients in remission than a single probiotic strain. Probiotic studies evaluating amelioration of symptoms in irritable bowel syndrome would require more sustained patient numbers. However, accumulated data is encouraging and suggests that efficacy is strain-dependent. Finally, too few probiotic intervention trials have been reported on colon cancer to allow any firm conclusion.

Clinical Trials as Topic↗

Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review.

BACKGROUND: The recent increase in the number and severity of cases of nosocomial Clostridium difficile-associated diarrhea (CDAD) has prompted interest in the use of probiotics for the prevention and treatment of this disease. We performed a systematic review of randomized controlled trials to assess the effectiveness of probiotic therapy. METHODS: We searched the PubMed, EMBASE, INAHTA, HEN and Cochrane Collaboration databases to identify trials in which the prevention or treatment of CDAD with probiotic therapy was the primary or secondary outcome. We extracted data on the number of patients randomly assigned to receive probiotic or placebo, the number of patients with CDAD, the type of probiotic, criteria for diagnosing CDAD, persistence of infection after treatment, compliance and adverse effects. RESULTS: We identified 4 eligible studies in which prevention (n = 1) or treatment (n = 3) of CDAD was the primary outcome. The benefit of probiotic therapy seen in 2 of the studies was restricted to subgroups characterized by severe CDAD and increased use of vancomycin. The remaining 2 studies were too methodologically flawed for us to draw meaningful conclusions. We also identified 4 trials in which prevention of antibiotic-associated diarrhea with probiotics was the primary outcome and prevention of CDAD a secondary outcome. These studies were limited primarily by too few CDAD cases and provided no evidence of effective prophylaxis. Overall, heterogeneity in choice and dose of probiotic and in criteria for diagnosing CDAD makes it difficult to synthesize information from the 8 studies. INTERPRETATION: Studies conducted to date provide insufficient evidence for the routine clinical use of probiotics to prevent or treat CDAD. Better designed and larger studies are needed.

Clostridioides difficile↗

Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials.

BACKGROUND: Antibiotic treatment is known to disturb gastrointestinal microflora, which results in a range of clinical symptoms--most notably, diarrhea. This is especially important in children, for whom antibiotics are prescribed frequently. Although meta-analyses have been conducted to evaluate the ability of probiotics to prevent antibiotic-induced diarrhea in the general population, little is known about which probiotic strains and doses might be of most benefit to children. Our objective in this study was to assess the efficacy of probiotics (of any specified strain or dose) for the prevention of antibiotic-associated diarrhea in children and to assess adverse events associated with the use of probiotics when coadministered with antibiotics to children. METHODS: A comprehensive search was performed of the major electronic databases (e.g., CENTRAL, MEDLINE, EMBASE, CINAHL, AMED) from their inception to January 2005. We also contacted experts and searched registries and meeting abstracts for additional relevant articles. Randomized controlled trials that compared probiotic treatment with placebo or no treatment, involving pediatric subjects less than 19 years of age were included. Two reviewers independently applied eligibility criteria and assessed the studies for methodological quality. Data were independently extracted by 2 reviewers and analyzed via the standard Cochrane methodology. RESULTS: Six studies were included (total n = 707 patients). The combined results, analyzed with a per-protocol method that reported on the incidence of diarrhea during antibiotic treatment, showed significant benefit for the use of probiotics over placebo (relative risk [RR] 0.43, 95% confidence interval [CI] 0.25-0.75, Iota2 = 70.1%). In contrast, results from intention-to-treat analysis were nonsignificant overall (RR 1.01, 95% CI 0.64-1.61). Subgroup analysis on 4 studies that provided at least 5 billion single-strain colony-forming units (CFUs) daily (range 5.5-40 x 10(9) Lactobacillus GG, L. sporogens or Saccharomyces boulardii) showed strong evidence with narrow CIs for the preventative effects of probiotics for antibiotic-associated diarrhea (RR 0.36, 95% CI 0.25-0.53, Iota2 = 3.5%). No serious adverse events were reported. INTERPRETATION: The potential protective effects of probiotics to prevent antibiotic-associated diarrhea in children do not withstand intention-to-treat analysis. Before routine use is recommended, further studies (with limited losses of subjects to follow-up) are merited. Trials should involve those probiotic strains and doses with the most promising evidence (i.e., Lactobacillus GG, L. sporogens or S. boulardii at 5-40 x 10(9) CFUs daily).

Adolescent↗

Use of probiotics in children with acute diarrhea.

Probiotics, defined as microbial cell preparations or components of microbial cells that have a beneficial effect on the health and well being of the host, have traditionally been used to treat and prevent a variety of infections. Beneficial effects of probiotics in acute infectious diarrhea in children seem to be: (i) moderate; (ii) strain-dependent; (iii) dose dependent; (iv) significant in watery diarrhea and viral gastroenteritis, but non-existent in invasive, bacterial diarrhea; and (v) more evident when treatment with probiotics is initiated early in the course of disease. Three large, randomized controlled trials (RCTs) provide evidence of a very modest effect (statistically significant, but of questionable clinical importance) of some probiotic strains (Lactobaccillus GG, Lactobaccillus reuteri, Bifodobacterium lactis) on the prevention of community-acquired diarrhea. We have found conflicting evidence from four RCTs on the efficacy of Lactobacillus GG and B. bifidum and Streptococcus thermophilus in the prevention of nosocomial diarrhea in children. Two RCTs in children provide evidence of a moderate beneficial effect of Lactobacillus GG in the prevention of antibacterial-associated diarrhea (AAD), but results in adults are conflicting. Data on the efficacy of other probiotic strains in AAD in children are very limited. In conclusion, to date, the most extensively studied and best documented clinical application of probiotics in children is for the treatment of acute watery diarrhea of rotaviral or presumably viral etiology. Studies documenting effects in other types of diarrheal diseases in children are limited, although some preliminary results are promising. The effects of different probiotic microorganisms are not equal. Only very few probiotic strains have been tested rigorously in RCTs. Many questions remain to be answered. Future clinical trials should evaluate carefully selected, precisely defined probiotic strains and address clinically important endpoints.

Acute Disease↗

The importance of guidelines in the development and application of probiotics.

Probiotics, defined as "Live microorganisms which when administered in adequate amounts confer a health benefit on the host" have many attributes including the lack of adverse side effects associated with their use. While probiotics have proven benefits, the optimism associated with their use is counterbalanced by the fact that many so-called "probiotic" products are unreliable in content and unproven clinically. Therefore much remains to be done to gain the acceptance of the broader medical community. Recognition of the obvious product inequality and the lack of any regulatory guidelines lead to the development of Operating Standards in 2002 (FAO/WHO), that would ensure product safety, reliability and a level playing field for all companies producing probiotic products. The guidelines constitute a set of parameters required for a product/strain to be termed "probiotic" and also the clinically relevant steps to be followed to move probiotics closer to being embraced by the medical community. These include i) implementation of Guidelines for use of probiotics; ii) phase I, II and III clinical trials to prove health benefits that are as good as or better than standard prevention or treatments for a particular condition or disease; iii) Good Manufacturing Practice and production of high quality products; iv) studies to identify mechanism of action in vivo; v) informative/ precise labelling; vi) development of probiotic organisms that can carry vaccines to hosts and/or anti- viral probiotics; vii) expansion of proven strains to benefit the oral cavity, nasopharynx, respiratory tract, stomach, vagina, bladder and skin as well as for cancer, allergies and recovery from surgery/ injury.

Drug Industry↗

[Probiotics based on live cultures of microorganisms].

The modern state of probiotic design and production was discussed in the survey. The worldwide data concerning types of probiotics and their use for restoration of resident microflora of hot-blooded animals and people were systematized. Much attention has been recently paid to the use of the natural preparations to maintain and regenerate the state of the resident microflora of animals and people. These preparations are known as probiotics. The term "probiotic" means microorganisms or substances which are capable to render sanitary effect on macroorganism. I. I. Mechnikov's concept on detoxifications of harmful substances formed in the digestive tract of men by probiotics is expounded. The modern concepts of the probiotics division into groups have been presented. Different kinds of industrial probiotics were considered. The mechanism of positive action of probiotics and their mutual relations with micro- and macroorganisms were provided. The scientific substantiation of new probiotic design was presented.

Animals↗

Probiotics. Some evidence of their effectiveness.

OBJECTIVE: To define the term probiotics, to indicate how to identify products that have been proven beneficial, and to assess the quality of evidence regarding probiotics. QUALITY OF EVIDENCE: A few level I studies support the effectiveness of specific probiotics for certain diagnoses. For most so-called probiotics, however, weak or no evidence supports their effectiveness. MAIN MESSAGE: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Level I evidence supports use of VSL#3 for maintaining remission of inflammatory colitis. Probiotics for treating vaginal infections, Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, have level I evidence of effectiveness, but are not available in Canada. Specific probiotics taken for certain indications improve health and have few side effects. CONCLUSION: Limited but good evidence supports the role of certain probiotics in medical practice. Because consumer pressure will undoubtedly stimulate further interest in probiotics, family doctors need to be informed about them so they can advise their patients appropriately.

Canada↗

Intestinal colonisation, microbiota and future probiotics?

The human intestine is colonized by a large number of microorganisms, collectively termed microbiota, which support a variety of physiological functions. As the major part of the microbiota has not yet been cultured, molecular methods are required to determine microbial composition and the impact of specific dietary components including probiotics. Probiotics are viable microbial food supplements, which have a beneficial impact on human health. Health-promoting properties have been demonstrated for specific probiotic products. The most significant demonstrations for probiotic efficacy include prevention and treatment of antibiotic associated diarrhea, rotavirus diarrhea and allergy prevention. Lactobacillus rhamnosus GG (=ATCC 53103) and Bifidobacterium lactis Bb12 are the among the best-characterized and most studied probiotic strains with demonstrated impact on human health. New complex targets for probiotics include irritable bowel syndrome and Helicobacter pylori infection. For future probiotics the most important target is a demonstrated clinical benefit supported by knowledge on the mechanistic actions in the microbiota of the target population. Molecular and genomics-based knowledge of the composition and functions of the microbiota, as well as deviations from the balanced microbiota, will advance the selection of new and specific probiotics. Potential combinations of specific probiotics may prove to be the next step to reduce the risk on intestinal diseases and reconstruct specific microbial deviations.

Bifidobacterium↗

Safety of probiotics.

New species and more specific strains of probiotic bacteria are constantly being sought for novel probiotic products. Prior to the incorporation of novel strains into food or therapeutic products a careful evaluation of their efficacy is required and an assessment made as to whether they share the safety status of traditional food organisms. Food organisms intrinsic to the production of traditional foods have been arbitrarily classified as safe in the absence of scientific criteria. Evidence for the safety and efficacy of probiotics has until recently been largely anecdotal or based on relatively little, and often poorly designed research. The demonstration of efficacy in probiotics offers vast opportunities for the development of human and veterinary products. The introduction of a new probiotic culture demands that it be at least as safe as its conventional counterparts. Many bacteria are being tested to find a putative probiotic, yielding conflicting data, sometimes for the same organism. Comparisons between studies and organisms cannot be readily made because of non-standardized dosing procedures. Information is not readily available on the equivalence of formulations for different probiotic preparations. There is vigorous debate on what constitutes appropriate safety testing for novel probiotic strains proposed for human consumption. Conventional toxicology and safety evaluation is of limited value in assessing the safety of probiotics. The addition of novel bacterial strains to foods and therapeutic products requires reconsideration of the procedures for safety assessment. This paper provides an overview of these issues.

Clinical Trials as Topic↗

Health benefits of probiotics.

This paper reviews the evidence for the claims of health benefits derived from the use of probiotics. A brief history of probiotics and the types of probiotics currently used and the criteria for the selection of probiotics is discussed. The ability of probiotics to enhance the nutritional content and bioavailability of nutrients and the scientific evidence for the usefulness of probiotics in alleviating the symptoms of lactose intolerance and in enhancing growth development is examined. The remainder of the review focuses on studies of a specific probiotic, Lactobacillus GG which has been extensively investigated for its health benefits in humans and animals. These studies severe as a model for the potential benefits of probiotics. The ability of Lactobacillus GG to treat or prevent diarrhoeal disease, to serve as an adjuvant for vaccines, to prevent rotavirus-induced diarrhoea, to prevent milk-based allergic reactions, alcohol-induced liver disease and colon cancer are presented. The review concludes with a discussion of the data supporting the safety of probiotics.

Animals↗

Probiotics in the new millennium.

Beneficial effects on human health by specific probiotic microorganisms such as prevention of gastrointestinal tract infections immune stimulation, and balancing of the intestinal microflora have been established in numerous clinical trials. The successful probiotic strains which are mainly members of Lactobacillus and more recently Bifidobacterium naturally found in the human intestinal tract, have been traditionally incorporated into fermented milk products but have excellent potential for further inclusion in functional foods and health-related products. While the health claims are generally accepted by both scientists and consumers, often the molecular mechanisms underlying the probiotic properties remains controversial. Further progress concerning the molecular basis of probiotic traits will give vital reinforcement to the probiotic concept and is a prerequisite for rational development into further applications. In this review, current research on the genetics of properties of the intestinal lactobacilli that may contribute to the activity and effectiveness of probiotics is described. The potential of molecular biology for future probiotic applications is addressed and a probiotic strains developed by modern biotechnology with advantages for specific consumers is presented.

Animals↗

Viability of human-derived probiotic lactobacilli in ice cream produced with sucrose and aspartame.

A mixture of human-derived probiotic strains of Lactobacillus acidophilus, L. agilis and L. rhamnosus was used as a probiotic culture in ice cream manufacture. Viability and survival of these probiotic cultures were investigated in two different ice cream formulations. Ice cream with sucrose and ice cream with aspartame were prepared and each of these was divided into two subgroups: one with direct addition of the probiotic culture and one with milk fermented by the same probiotic culture. Ice cream samples were stored at -20 degrees C for 6 months and the survival rate of cultures were determined monthly. Probiotic cultures underwent tests for resistance to bile salts, antibiotics, acidic conditions; they were found to be highly resistant to such challenges. Chemical analysis of ice cream samples, such as determination of acidity, pH and solid matter, was also performed. The probiotic cultures remained unchanged in ice cream stored for up to 6 months regardless of the sweeteners used. Using probiotic cultures in ice cream mixes did not alter the characteristics of the product.

Aspartame↗

Effects of exopolysaccharide-producing probiotic strains on experimental colitis in rats.

PURPOSE: Inflammatory bowel disease is suggested to result from a dysregulated immune response toward intestinal microflora, which may be restored by probiotic therapy based on the concept of healthy microflora. Ideal probiotic bacteria may be beneficial in inflammatory bowel disease; however, the mechanism of action and the clinical efficacy of probiotic usage are still unclear. In the present study, the effect of exopolysaccharide producing probiotics was evaluated on an experimental colitis model in rats. METHODS: Colitis was induced by intracolonic administration of acetic acid. Then, rats were treated daily with two probiotic strains, Lactobacillus delbrueckii subsp. bulgaricus B3 strain (exopolysaccharide of 211 mg/l: high-EPS group) or Lactobacillus delbrueckii subsp. bulgaricus A13 strain (EPS of 27 mg/l: low-EPS group), which were given into the stomach. The non-colitis-fed control group was only treated with high-exopolysaccharide strain. The model-control and control groups were treated only with tap water. Rats were killed after a seven-day treatment period. Disease activity was quantified by use of histologic scores and colonic myeloperoxidase activity, which is a marker of neutrophil infiltration during inflammation. RESULTS: The enhanced inflammatory response was accompanied by a higher level of myeloperoxidase activity in the colitis group. Histologic scores of colonic damage and myeloperoxidase activity were lower in both probiotic-treated groups compared with those of the colitis control group (P<0.001), although the mentioned scores improved significantly more in the high-EPS group than in the low-EPS group (P<0.001). CONCLUSIONS: Exopolysaccharide-producing probiotics significantly attenuate experimental colitis, which may be mediated by exopolysaccharide in a dose-dependent manner. Therefore, exopolysaccharide-producing probiotics may be a promising therapeutic role in inflammatory bowel disease.

Acetic Acid↗

Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.

BACKGROUND: Despite preliminary evidence, the role of probiotics in allergy prevention is unclear. OBJECTIVE: To determine whether early probiotic supplementation prevents allergic disease in high-risk infants. METHODS: Newborns of women with allergy (n = 231) received either Lactobacillus acidophilus (LAVRI-A1) or placebo daily for the first 6 months of life. Children were assessed for atopic dermatitis (AD) and other symptoms at 6 and 12 months and had allergen skin prick tests (SPT) at 12 months of age. RESULTS: A total of 178 infants completed the supplementation period. Those in the probiotic group showed significantly higher rates of Lactobacillus colonization (P = .039). At 6 months, AD rates were similar in the probiotic (n = 23/89; 25.8%) and placebo (n = 20/88; 22.7%) groups (P = .629). There was also no difference at 12 months, although the proportion of children with SPT+AD was significantly higher in the probiotic group (P = .045). At 12 months, the rate of sensitization was significantly higher in the probiotic group (P = .030). The presence of culturable Lactobacilli or Bifidobacterium in stools in the first month of life was not associated with the risk of subsequent sensitization or disease; however, the presence of Lactobacillus at 6 months of age was associated with increased risk of subsequent cow's milk sensitization (P = .012). CONCLUSION: Early probiotic supplementation with L acidophilus did not reduce the risk of AD in high-risk infants and was associated with increased allergen sensitization in infants receiving supplements. The long-term significance of the increased rate of sensitization needs to be investigated in further studies. CLINICAL IMPLICATIONS: These findings challenge the role of probiotics in allergy prevention.

Allergens↗

Selection and design of probiotics.

Over the past 5 years the probiotic field has exploded with a number of new cultures, each purported to elicit a variety of benefits. Lists of functional characteristics and benefits, in vivo, are now commonplace to any presentation on probiotics. Scientifically established health claims remain among the highest priorities to companies who seek to establish solid health benefits that will promote their particular probiotic. The scientific community faces a greater challenge and must objectively seek cause and effect relationships for many potential and currently investigated probiotic species and strain combinations. Rational selection and design of probiotics remains an important challenge and will require a platform of basic information about the physiology and genetics of candidate strains relevant to their intestinal roles, functional activities, and interactions with other resident microflora. In this context, genetic characterization of probiotic cultures is essential to unequivocally define their contributions to the intestinal microbiota and ultimately identify the genotypes that control any unique and beneficial properties. Strain selection and differentiation, based on the genetic complement and programming of a candidate probiotic, then becomes feasible. Looking ahead, it will be vital to the development of this exploding field to correlate important characteristics in probiotics with known genotypes and regulatory controls that are likely to affect functionality and beneficial outcomes, in vivo.

Base Sequence↗

Pseudo-outbreak of toxigenic Bacillus cereus isolated from stools of three patients with diarrhoea after oral administration of a probiotic medication.

From December 2000 to January 2001 toxigenic Bacillus cereus was isolated from stools of three patients with diarrhoea at two tertiary hospitals in southwest Germany. Two cases with nosocomial diarrhoea were apparently epidemiologically related (same time and ward), a third case was unrelated with respect to time and location. In order to investigate the epidemiology of these three cases, clinical isolates and isolates from an unexpected, possible common source (probiotic medication) were compared by toxin assay, biotyping and randomly amplified polymorphic DNA (RAPD) analysis. The three clinical isolates, as well as the two isolates from different lots of the probiotic medication (Bactisubtil containing 'Bacillus IP 5832'; Cassella-med, Cologne, Germany), were indistinguishable by toxin assay, biotyping and RAPD, when compared with other distinguishable clinical B. cereus strains. As the diarrhoeal disease had begun before the probiotic medication had been administered to overcome it, the isolated B. cereus probably was at least initially, not the cause of the observed diarrhoeal disease. Isolation of toxigenic B. cereus from stools appeared to be a diagnostically misleading epiphenomenon after oral medication with the probiotic. We conclude, that probiotic medication with Bactisubtil (Bacillus IP 5832) may result in diagnostically misleading results when culturing stool specimens from patients with diarrhoea. The clonal identity of isolates may be misinterpreted as an outbreak. Stool specimens should be taken before start of probiotic treatment and clinicians should state probiotic medication when ordering stool examinations to allow correct interpretation of results. Nevertheless, it is noteworthy that a probiotic medication contains potentially toxigenic material.

Adjuvants, Immunologic↗

Probiotics in the third millennium.

Probiotics are "living microorganisms which upon ingestion in certain numbers exert health benefits beyond inherent general nutrition". Since 1987, when the first publication on the properties of the Lactobacillus GG was done, overall, there have been over 200 publications in peer-reviewed scientific journals. This paper will report the status and the prospectus of probiotics research at the beginning of the Third Millennium. Probiotics have proven benefits in treatment and prevention of rotavirus diarrhoea in children and reduction of antibiotic-associated intestinal side-effects. Interesting results have recently been published regarding food allergies and atopic eczema in children. Prevention of vaginitis and of travellers' diarrhoea have also been reported. Promising results are being reported in patients with inflammatory bowel disease, cystic fibrosis, dental caries and irritable bowel syndrome. It has also been suggested that probiotics could enhance oral vaccine administration, and that they may help treatment against Helicobacter pylori infection, but further studies are needed. Future areas of research regard probiotics' role in the process of carcinogenesis, given their influence on the gut microflora, and as immune modulators in autoimmune disorders. The possibility of introducing appropriate genes to the probiotics to make them produce various compounds is also under investigation. However, there is still confusion in the minds of the authorities over whether a probiotic is a drug, a food, or a dietary supplement. The challenge is to continue research to define the appropriate uses of probiotics and discover new applications which will bring benefit to humankind.

Bifidobacterium↗

Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice.

BACKGROUND: The enteric bacterial flora has been implicated in the pathogenesis of enterocolitis and colon cancer in C57BL/6 IL-10 knockout mice. Probiotic Lactobacilli modify the enteric flora and are thought to have a beneficial effect on enterocolitis. We conducted a controlled feeding trial in IL-10 knockout mice using the probiotic Lactobacillus salivarius ssp. salivarius UCC118. AIM: To determine the effect of probiotic consumption on the gastrointestinal microflora, tumour development and colitis in IL-10 knockout mice. METHODS: Twenty IL-10 knockout mice were studied (10 consumed probiotic organisms in milk and 10 consumed unmodified milk) for 16 weeks. Faecal microbial analysis was performed weekly to enumerate excretion of the probiotic UCC118, total lactobacilli, Clostridium perfringens, bacteroides, coliforms, bifidobacteria and enterococci. At sacrifice, the small and large bowel were microbiologically and histologically assessed. RESULTS: L. salivarius UCC118 was detected in faeces from all mice in the probiotic fed group, but not the control group. Faecal coliform and enterococci levels were significantly reduced in probiotic fed animals compared to the controls (P < 0.05). At sacrifice, a significant reduction in C. perfringens numbers was observed in the test mice (P < 0.05). There were no fatalities in the test group compared to two deaths from fulminant colitis in the control group. Only one test mouse developed colonic adenocarcinoma compared to five in the control group. Test animal mucosal inflammation consistently scored lower than that of the control mice. CONCLUSION: In this placebo controlled trial, modification of enteric flora in IL-10 knockout mice by probiotic lactobacilli was associated with reduced prevalence of colon cancer and mucosal inflammatory activity.

Animals↗