Probiotics and prebiotics. International clinical guidelines for probiotics

REVIEW OF CLINICAL GUIDELINES FOR MEGAEL-DENA COMPONENTS

The volume of research on probiotics has steadily increased over the first 15 years of this century and probiotics are increasingly available to consumers, mostly as food supplements. 

The graph demonstrates the number of publications with Google Scholar search containing the word “probiotics” and the general term “intestine” in their titles over the last 25 years. While the number of publications using the general term "intestine" has remained steady, a robust increase in the number of publications on probiotics is observed in the 21st century.

Although the beneficial effects of probiotics and prebiotics in patients with various conditions are supported by a number of clinical studies (recently reviewed by McFarland [1]), regulation of the use of probiotics and prebiotics is complicated by several factors.

First, the complexity of the indigenous microflora (also called commensal microbiota) is not yet fully characterized, in part because only a limited proportion of intestinal microorganisms can be identified by traditional culturing [2].

Second, the best species/strains or combinations of probiotics for particular conditions are not yet defined, although in some cases circumstantial evidence suggests that particular species are more efficient than others (for example, one of the components of Megael-Dena, Lactobacillus rhamnosus, appears to be more efficient than other probiotic species in patients with atopic dermatitis [3, 4]).

Third, although several mechanisms of action of probiotics have been suggested, such as direct competition with pathogenic microorganisms or modulation of immune responses [5, 6], the actual mechanisms in particular cases of successful use of probiotics remain mostly hypothetical.

In 2001−2002, a working group of experts from 11 countries (Argentina, Canada, Chile, Finland, France, Ireland, Italy, New Zealand, Sweden, Switzerland, and the USA) developed guidelines on “properties, functionality, benefits, safety, and nutritional features of probiotic foods” (primarily those containing lactic bacteria, which are mostly used as probiotics) on behalf of the Food and Agriculture Organization (FAO) of the United Nations and the World Health Organization (WHO) to assist governments in developing their own regulations on health claims regarding probiotics. The latest edition of these guidelines (2006) [7] is also used for training purposes by the United Nations Educational, Scientific and Cultural Organization (UNESCO) [8]. The guidelines adopted a definition of probiotics as “live microorganisms which when administered in adequate amounts, confer a health benefit on the host,” (although currently there is no universally accepted definition of probiotics and a number of slightly different definitions are in use [9]) and recommended that the guidelines be promoted at an international level and followed for any bacterial strain called “probiotic”. They also recommended development of the regulations “to allow specific health claims on probiotic food labels in cases where scientific evidence exists,” and applying good manufacturing practices (GMP) to the manufacture of probiotic foods. Some studies on which these guidelines were based were pilot studies conducted on a small number of patients. For example, the working group cited a study by Biller et al. [10] conducted in the USA. The authors used supplementation with Lactobacillus rhamnosus (one of the components of Megael-Dena) in four children (aged between five months and five and a half years) who had undergone antibacterial therapy for Clostridium difficile infection but still had several relapses of the infection. The study found that all patients became asymptomatic two weeks after starting the probiotic and two of them had no further relapses; two other patients had relapses and were given the same probiotic again, after which they remained asymptomatic [10]. Some publications referred to by the FAO/WHO working group were larger scale placebo-controlled studies, such as the one by Kalliomäki et al., conducted in Finland [11]. This was a double-blind, randomized placebo-controlled trial of L. rhamnosus, which involved 132 expectant mothers whose children were considered at risk of atopic allergy, as well as their children born in the course of the study. Mothers were given the probiotic pre- and postnatally (for six months). The authors found that the incidence of atopic eczema was halved in the probiotic group in comparison with the placebo group [1].

Because of a high variability in the design of such studies, which hampered cross-study analysis, the FAO/WHO working group recommended following the standard methods for clinical evaluations, i.e. Phase 1 trials to assess safety, Phase 2 (randomized, double-blind, placebo-controlled studies to assess the efficacy and measure adverse effects), Phase 3 (effectiveness), and finally Phase 4 (surveillance). Clinical studies should use sample sizes calculated for specific endpoints and perform appropriate statistical tests to establish statistically significant differences.

Most probiotics are sold as foods or food supplements and thus only general health claims are allowed. The FAO/WHO working group recommended allowing more specific health claims when they are supported by sufficient scientific evidence, with product manufacturers’ claims being verified by independent experts. In this respect, current guidelines differ in different countries. In the USA, probiotics are available as dietary supplements; only “structure/function” health claims are allowed by the United States Food and Drug Administration (FDA), i.e. claims that the supplement affects “the structure or function in humans” or the claims of the documented mechanism of such action [12]. Such claims can be, but do not necessarily need to be, approved by the FDA [9]. In the USA, probiotics cannot be formally considered to cure or treat any diseases [1], even if this is supported by clinical trials (however, particular health organizations may issue their own guidelines, see below). Studies that intend to demonstrate such effects of probiotics are subject to restrictive regulations (normally applied to new drug trials) by the FDA Center for Biologics Evaluation and Research; this has reportedly hampered such studies in the US [9].

Specific claims regarding the use of probiotics to prevent or cure diseases are formally allowed in European countries and have to be substantiated by properly conducted human trials in the targeted population or in healthy volunteers [1]. However, most of such applications have been rejected by the European Food Safety Authority (EFSA) [1, 9, 13], in part because it judged the scientific evidence to support specific health claims insufficient or based on indirect effects [14]. In 2011, the EFSA issued detailed requirements for health claims related to gut and immune function, including claims related to the gastrointestinal microbiota [15]. In the document, the EFSA concluded that it was not satisfied by the existing evidence that “increasing the number of any groups of microorganisms, including lactobacilli and/or bifidobacteria” has beneficial physiological effects. The same year, in order to facilitate the approval by the EFSA of claims related to the use of probiotics for specific diseases and pathological conditions, an international panel of experts from nine European Union countries published suggested guidelines on the design of probiotic studies intended to substantiate such specific health claims [13]. The ruling by the EFSA has been considered by some authors as controversial but will likely result in a more rigorous approach to the design of clinical studies on the effects of probiotics and prebiotics [16, 17].

Finally, it should be noted that some health organizations have issued their own evidence-based guidelines on the use of probiotics. For example, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the European Society for Paediatric Infectious Diseases (ESPID) published guidelines for the management of acute gastroenteritis in children [18]. The authors of these guidelines note that out of many available probiotic microorganisms only two species have been proven to be efficient for acute gastroenteritis patients (in combination with rehydration therapy). One of these probiotics is the Megael-Dena component L. rhamnosus [18]. These conclusions were based on a review of several published meta-analyses of clinical trials. Similarly, the Cincinnati Children's Hospital guidelines recommend using L. rhamnosus in children with acute gastroenteritis [19] and outline the optimal conditions (treatment should be started as soon as possible at a dose of at least 1010 colony-forming units per day, and continued for 5–7 days). These recommendations are mainly based on two reviews of clinical studies [20, 21] and the above ESPGHAN/ ESPID guidelines.

The University of Texas at Austin considers that “there is high certainty that the benefits [of probiotics and prebiotics] are substantial” in patients undergoing antibiotic therapy to eradicate Helicobacter pylori [22]. The recommendation of this university to use probiotics in such patients is based on a published meta-analysis of 34 randomized double-blind, placebo-controlled trials (4,138 patients in total), which found that the pooled relative risk of antibiotic-associated diarrhea was reduced by ~50% by probiotic supplementation [23], and a review by Boyanova and Mitov who note that several species of Lactobacillus and Bifidobacterium (seven out of eight bacterial species included in Megael-Dena belong to these genera) are beneficial for patients undergoing antibiotic therapy [24].

The American Academy of Pediatrics has published guidelines on the efficiency and safety of probiotic and prebiotic products in pediatric patients, which are based on an extensive review of published clinical studies [25]. The guidelines point out that probiotics are effective for treatment of acute viral gastroenteritis and prevention of antibiotic-associated diarrhea and possibly a number of other conditions in healthy children, but should be used with caution in immunocompromised or chronically debilitated children because of possible complications. The guidelines of the British Society of Gastroenterology point out that there is evidence of benefit of probiotics in maintenance and treatment of ulcerative colitis but not Crohn’s disease [26].

The World Gastroenterology Organisation (WGO) has issued detailed guidelines on the use of probiotics and prebiotics [27] as part of its “Global Guidelines.” In particular, the WGO guidelines recognize the effectiveness of such Megael-Dena components as Lactobacillus casei and L. rhamnosus in treatment of acute infectious diarrhea, Bifidobacterium lactis, L. rhamnosus, and Streptococcus thermophilus in prevention of antibiotic-associated and nosocomial diarrhea, B. lactis and L. casei in prevention of common community-acquired gastrointestinal infections, L. casei as adjuvant therapy during H. pylori eradication therapy, and L. acidophilus, L. casei, B. bifidum, and oligofructose (fructooligosaccharides) in prevention of Clostridium difficile–associated diarrhea [27]. In the USA, the WGO guidelines have been endorsed in a review commissioned by the American College of Gastroenterology [28].

References

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