In addition to providing an updated definition of probiotics, the Expert Panel of the United Nations and the World Health Organization (WHO) also developed guidelines to describe what is meant by the term ‘probiotic’ (25
). This necessitates proper identification and classification of the organisms, suitable and shelf-stable formulation, appropriate randomized clinical efficacy evidence, and safety assessment. Unfortunately, many so-called probiotics do not meet these criteria, and indeed too many have been shown to contain wrongly labelled organisms, contaminants or significantly fewer viable cells than required (27
). This makes it difficult to then assess reviews and meta-analyses of probiotics, because undocumented strains and products are often not excluded from these assessments. Nevertheless, the Food and Agriculture Organization (FAO) and WHO, as well as numerous reviews have stated that there is sufficient evidence to show that pro-biotic strains can help prevent and treat diarrheal episodes, and enhance intestinal health (1
). The most documented strains for these effects are Lactobacillus rhamnosus
GG, Lactobacillus reuteri
SD2112, and Saccharomyces cerevisiae
The question of how the efficacy of probiotics is evaluated, overall, is somewhat contentious and certainly not an easy one to answer. In addition to only including properly produced and clinically documented products, issues of study design, patient pool, sex, duration, dosage and delivery form all come into play. In addition, when assessing the use of probiotics or any other remedy to prevent diarrhea, it is easy to standardize the antibiotics used, but not the exposure rates to different gastrointestinal pathogens. This is especially true for traveller’s diarrhea. Failure to show probiotics being effective for this problem could be explained by differences in exposure to pathogens, as well as by the authors of the meta-analysis, including completely unproven products such as BD Lactinex (Becton, Dickinson and Company, USA) (35
In a meta-analysis of six randomized, placebo-controlled trials of 766 children, treatment with probiotics compared with placebo reduced the risk of antibiotic-associated diarrhea (AAD) from 28.5% to 11.9% (RR 0.44, 95% CI 0.25 to 0.77, random effects model) (36
). A preplanned subgroup analysis showed that a reduction in the risk for AAD was associated with the use of L rhamnosus
GG (two randomized, controlled trials [RCTs] with 307 participants; RR 0.3, 95% CI 0.15 to 0.6), S cerevisiae
lyo (one RCT with 246 participants; RR 0.2, 95% CI 0.07 to 0.6) or Bifidobacterium lactis
plus Streptococcus thermophilus
(one RCT with 157 participants; RR 0.5, 95% CI 0.3 to 0.95). Of these, only S cerevisiae
lyo is available in Canada (as Florastor, Medical Futures Inc, Canada).
A Turkish study of 151 patients showed a significant reduction in AAD (1.4% versus 9%; P<0.05) with S cerevisiae
lyo daily treatment given along with antibiotics (37
). In a Polish study, 269 children (aged six months to 14 years) with otitis media and/or respiratory tract infections were enrolled in a double-blind, randomized, placebo-controlled trial to receive standard antibiotic treatment plus 250 mg of S cerevisiae
lyo orally twice daily for the duration of antibiotic therapy (38
). The prevalence of acute watery diarrhea (three or more loose or watery stools per day for 48 h or longer, occurring during or up to two weeks after the antibiotic therapy) was significantly lower in the probiotic group (8% versus 23%; RR 0.3, 95% CI 0.2 to 0.7). The S cerevisiae
lyo also reduced the risk of AAD caused by C difficile
(3.4% versus 17.3%).
A study of 50 children in Pakistan with the same average frequency of stools in S cerevisiae
lyo and control groups at the time of inclusion in a randomized study, showed an effect of probiotics by day 3. There was a reduction from 4.2 to 2.7 stools per day, and by day 6, the number of stools per day went down to 1.6, compared with 3.3 stools per day with the placebo (39
). The duration of diarrhea was 3.6 days in the S cerevisiae
lyo group versus 4.8 days in the control group (P=0.001). Over the following two months, the probiotic-treated children had a significantly lower frequency of episodes (0.54) than the control group (1.08).
There are preliminary data from a 25-patient study suggesting that S boulardii
given three times daily, along with mesalazine to patients suffering from mild-to-moderate clinical flare-up of UC, can help with clinical remission (17 of 25 patients attained remission) (40
). Further studies are warranted with this probiotic for UC and other more complicated gastrointestinal patients. During such use of the product, staff need to be trained in handling these live organisms, because some cases of fungemia have resulted through contamination of intravenous lines, as well as possible gut translocation (41
). Particular care is needed for immune-suppressed and critically ill patients to reduce the risk of fungemia.
In an effort to globally examine the usefulness of probiotics to prevent diarrhea, McFarland (42
) pooled heterogenous studies. This meta-analysis concluded that probiotics could be effective in some cases, including the prevention of relapse following successful antibiotic treatment of C difficile
diarrhea. Dendukuri and Brophy (43
) and Lewis (44
) criticized the analysis for the pitfalls of comparing studies with different strains, outcomes, doses and duration of treatment, and for including adults and children. The latter inflated the potential side effects of probiotics, as did Segarra-Newnham (45
) based on a serious lack of evaluation of the literature and understanding of probiotics, and failure to cite various safety reports (46
). Furthermore, safe use of L rhamnosus
GG and GR-1 in HIV and IBD patients (48
) counters Lewis’s unsubstantiated opinion that probiotic strains are potentially hazardous. Lewis (44
) concluded that he was not convinced that probiotics could reduce the recurrence of C difficile
; however, in a rebuttal, McFarland (51
) re-explained and reaffirmed her initial findings.
Readers of these papers need to make their own conclusions as to the merits of L rhamnosus GG and S cerevisiae subspecies boulardii lyo in preventing diarrhea. For our part, we side with the viewpoint of McFarland, but believe that further studies are needed on patients who are already infected with C difficile, because such cases have still not been proven conclusively to be more effectively cured by the addition of probiotics.
In terms of management of patients seen by gastroenterologists in Canada, a longer discussion will follow. But, for subjects who are without any underlying gastrointestinal disorders and travelling to the developing world or receiving antibiotics, it seems reasonable to use either L rhamnosus GG or S cerevisiae subspecies boulardii lyo to attempt to prevent or reduce the severity of diarrhea, albeit only the latter product is available in Canada (as Florastor).
The case in favour of probiotics to augment the cure of bacterial and viral diarrheal disease is quite convincing, especially in children who are coadministered with oral rehydration. In general, the duration of the condition is shortened by one to two days, or in some cases, more (52
With respect to IBS, a recent review suggested that there is a rationale for using probiotics to correct a dysfunctional relationship between the indigenous flora and the host (57
). While studies with Bifidobacterium infantis
35624 show relief of some symptoms of IBS (58
), VSL#3 (VSL Pharmaceuticals Inc, Canada) (discussed in more detail below) reduces flatulence scores and retards colonic transit (60
), further studies with these and other strains are needed to determine dosage, duration and extent of clinical benefits across the spectrum of IBS complaints.
Although Helicobacter pylori
is not a pathogen commonly found in the stomach of Canadians, it is a major cause of ulcers and cancer in other parts of the world, especially in Asia. A number of studies have been performed to assess the use of probiotics against H pylori
. For the most part, there is little conclusive evidence to indicate that probiotics can eradicate H pylori
on their own. However, there are some data to indicate that certain probiotics can either augment reduction in symptoms, or reduce the side effects of antibiotic therapy. Two examples are given. In a randomized, double-blind, placebo-controlled study, 79 subjects received 12 weeks of placebo or Bifidobacterium bifidum
YIT 4007 fermented milk. There was improvement in upper gastrointestinal symptoms (62
). In a study of 40 H pylori
-positive children (median age 12.3 years) who were consecutively treated with 10-day sequential therapy (omeprazole plus amoxicillin for five days, and omeprazole plus clarithromycin plus tinidazole for another five days), and blindly randomly assigned to receive either L reuteri
ATCC 55730 (1×108
colony-forming units) or placebo, there was a significant reduction in the Gastrointestinal Symptoms Rating Scale score during eradication therapy (4.1±2 versus 6.2±3; P<0.01) and at the end of follow-up (3.2±2 versus 5.8±3.4; P<0.009) (63