Medeiros, José A. MD, PhD*; Pereira, Marta-Isabel MD*,†
Helicobacter pylori infection in humans is associated with a spectrum of gastroenterologic and hematologic diseases including chronic gastritis, peptic ulcers, gastric adenocarcinoma, gastric mucosa–associated lymphoid tissue lymphoma, sideropenic anemia, and primary immune thrombocytopenia. Successful eradication of the bacterium is a major component in the treatment of these conditions.
However, despite the cost of therapy, the rates of eradication after triple therapies are decreasing, with standard amoxicillin plus clarithromycin-based triple therapy achieving eradication rates of only about 75% in many series, albeit with an apparent geographic variation, in agreement with differing patterns of antibiotic resistance throughout the world.1–3 Quadruple second-line therapy has, likewise, resulted in unsatisfactory eradication rates.
Although unsuccessful eradication can be due to increasing antimicrobial resistance, an additional important contributor is the high incidence of treatment-related side effects (including diarrhea, nausea, epigastric discomfort, and dysgeusia with a metallic taste), determining low compliance, and, consequently, incomplete therapy. Many of these gastrointestinal effects result from the modification of the ecologic equilibrium of intestinal microbiota due to the antibiotics.4
The identification of alternative therapeutic strategies to overcome these limitations is a pressing issue. Although altering the duration of treatment or the choice of first-line antibiotics can target resistance patterns, lack of adherence to treatment because of adverse events has been addressed mostly through the addition of probiotics to eradication regimens, in an attempt to reestablish the gastrointestinal microbial equilibrium.
Probiotics are live nonpathogenic microbial food products or supplements whose interaction with the host can benefit the health status of the latter, mostly through the modulation of the balance of its microflora, although direct antimicrobial effects have been described by some groups.5
Probiotic bacteria are able to survive in the gastrointestinal tract despite the administration of antimicrobial eradication regimens, as shown by the recovery of probiotics from the feces of treated patients.6 In addition, it has been demonstrated that the supplementation of eradication protocols with probiotics does impact the intestinal microflora. Whereas triple therapy results in significant increases in the facultative anerobe component of the microflora after the start of treatment, the addition of Lactobacillus acidophilus and Bifidobacterium bifidum midtreatment reverts this increase back to starting levels, and the addition from the start maintains a stable facultative anerobe population throughout treatment and follow-up.7 Similarly, although the percentage of bifidobacteria in anerobes in the stool is significantly decreased by triple therapy, supplementation with an L. acidophilus-containing and B. lactis-containing yogurt is able to restore the population of bifidobacteria to pretreatment levels.8
Apart from the modification of gastrointestinal microflora, which can be harnessed to reduce treatment-associated side effects, probiotics have also been shown to exert direct inhibitory effects on H. pylori in both in vitro and in vivo animal models, with the potential to improve eradication rates. These effects have been demonstrated for several species of probiotics, including L. acidophilus, L. salivarius, L. rhamnosus, and B. bifidum, among others.9–11
Proposed mechanisms underlying the beneficial interaction between probiotics and H. pylori, and the modulation of the colonization of the gastric mucosa by the latter, include the production of lactic acid with H. pylori inhibition because of decreasing gastric pH; the direct killing of H. pylori through secreted metabolites with antimicrobial properties, including bacteriocins, autolysins, and organic acids; the interference with H. pylori adhesion to epithelial cells, both through the secretion of antimicrobial molecules and through direct competition for adhesion; and the ability to reduce H. pylori-induced gastritis through the stabilization of the mucosal barrier, the secretion of mucins, and the modulation of the host immune response to the infection. These mechanisms have been amply reviewed in the literature over the past decade.10,12–16
Despite this theoretical foundation justifying the use of probiotics as adjuncts to eradication therapy, published clinical trial data have yielded dissonant results, and probiotic supplementation remains a controversial issue.
In fact, the definition of “probiotic” includes a wide range of microbial species, an aspect that can partially help explain the contradictory results obtained in different trials, because of the use of distinct probiotic strain combinations. The method, dose, and timing of supplementation, likewise, vary markedly among studies, with some authors on one end of the spectrum using multistrain milk-based fermented preparations (including yogurt and kefir) and on the other end using pure single-strain supplementation in capsule form.17,18 Whereas some authors have reported starting probiotics as much as 4 weeks before eradication, few have restricted supplementation for the duration of the eradication therapy, and others prolong it for as long as 4 or even 8 weeks after therapy.8,18–20
The lack of protocol standardization is not the only problem, and difficulties in interpretation of the various results are compounded by the type of analysis performed and the outcomes that are measured. Whereas some groups have primarily looked at the incidence or severity of side effects, others have focused on eradication rates; in the latter case, results can additionally be reported either through an intention-to-treat analysis or a per-protocol analysis. A final problem contained in the current literature is the number of pilot studies and trials with small sample sizes, which might not be adequately powered to find small differences in eradication rates or in the frequency of individual adverse events.
Despite the contradictory results, some considerations can be made regarding the existing literature. Although direct anti-H. pylori effects have been described, the present data do not appear to support the isolated use of probiotics as an alternative to eradication therapy, as no trial has been able to conclusively demonstrate successful eradication of H. pylori infection by probiotic treatment alone,13,16 although a recent pilot study reports that treatment with an association of 8 species of probiotics resulted in H. pylori negativity in 13 of 40 H. pylori-positive dyspeptic patients.21
In fact, in vitro results do not seem to translate to in vivo efficacy, as shown with a multistrain yogurt containing L. acidophilus, L. casei, L. bulgaricus, and Streptococcus thermophilus strains with in vitro inhibitory effects on H. pylori, which did not successfully eradicate H. pylori in asymptomatic women.22
Nevertheless, probiotics have been shown to be able to reduce the gastric load of the pathogen, theoretically facilitating eradication by subsequent antimicrobial regimens.12 However, although L. reuteri was able to reduce the intragastric H. pylori load before sequential eradication treatment—with a significant reduction in dyspepsia—eradication rates were not affected.23
Systematic reviews of the literature have shown that various probiotic species (including Lactobacillus spp., Bifidobacterium spp., Saccharomyces spp., and Bacillus spp.20,24) can help diminish eradication-related side effects, including diarrhea, nausea, dyspepsia, and dysgeusia, increasing tolerability and, therefore, compliance. It has been postulated that it is this increase in the number of patients completing the therapy as prescribed that could, in turn, lead to higher eradication rates.16,25,26 However, a series of patients treated with sequential therapy demonstrated that, although the addition of probiotics increased compliance through the decrease in treatment-associated symptoms, there was no effect on eradication rates.27 In contrast, a meta-analysis of 14 randomized trials comparing probiotic supplementation to placebo or no-intervention found that probiotics increased eradication rates and decreased antibiotic-related side effects.28 One of the main limitations of this analysis was the inclusion of several different probiotics, which could be unequally effective.
Considering lactobacilli, data remain contradictory. In 2009 a meta-analysis of 8 randomized trials on the supplementation of triple therapy with lactobacilli showed a benefit in eradication rates (by an intention-to-treat analysis), with a decrease in diarrhea, bloating, and dysgeusia.9 This is supported by the recent report that the eradication rate with second-line levofloxacin-based therapy was significantly improved by supplementation with L. reuteri, with a decrease in the incidence of nausea and diarrhea.4 L. reuteri has also been reported to decrease therapy-associated side effects in children undergoing sequential therapy, both during eradication therapy and at follow-up.29 Nevertheless, a comparison of standard 7-day therapy, standard 7-day therapy plus L. reuteri supplementation, and standard 7- or 14-day therapy plus a high-concentration probiotic mixture achieved statistically similar eradication rates of <80% for all groups, with no differences in the incidence of side effects.1
Similarly, in our own series, in 2011, we found that the addition of L. acidophilus to standard triple therapy did not influence eradication rates.18 However, a combination of L. acidophilus with L. rhamnosus was shown to increase the eradication rate of standard triple therapy.30 In contrast, although the addition of L. rhamnosus to triple therapy, in adults, decreased the incidence of diarrhea, nausea, and dysgeusia, and increased treatment tolerability, in pediatric patients it did not significantly alter the eradication rate or side effects.31,32 In patients resistant to first-line therapy, the supplementation of quadruple therapy with L. casei was able to reduce treatment-associated side effects.33
The bifidobacteria have also been the subject of trials in eradication therapy. Although the addition of B. animalis-containing yogurt to standard triple therapy did not improve eradication rates, it was found to reduce the incidence of stomatitis and of constipation.14 The majority of trials analyzing bifidobacteria, however, have used associations with lactobacilli, especially in milk products. In fact, yogurt containing live L. acidophilus and B. lactis was associated with a significantly reduced mean number of days with antibiotic-associated diarrhea (but not with its frequency), compared with the same yogurt with killed bacteria, and with milk acidified with lactic acid, supporting an active role for the live bacteria.19 It was shown that the twice-daily ingestion of L. acidophilus and B. lactis-containing yogurt over a period of 6 weeks decreased the gastric H. pylori bacterial load, when compared with a milk-based placebo; nevertheless, in vitro, only the Bifidobacterium strain showed H. pylori-inhibitory effects.34 The supplementation of triple therapy with L. acidophilus and B. lactis-containing yogurt increased the eradication rate by intention-to-treat analysis; by per-protocol analysis, the eradication rate was identical to the no-intervention group, suggesting that it improves eradication by increasing compliance and the number of patients who effectively complete the treatment protocol.8 However, when used as pretreatment to second-line quadruple therapy, this yogurt also significantly decreased the gastric H. pylori load, increasing the eradication rate, compared with quadruple therapy alone.35 Other alternative lactobacilli-bifidobacteria associations have also been reported to increase the eradication rate of standard triple therapy.36
Another group of studies has described positive results with Saccharomyces boulardii, which was shown in a meta-analysis of 5 randomized trials to significantly increase the eradication rate of standard triple therapy and decrease the incidence of therapy-related side effects, most notably diarrhea.37 Even dissenting trials that suggested it did not improve the eradication rate of standard 14-day eradication therapy found that the incidence of diarrhea and of epigastric discomfort were reduced, as were posttreatment dyspepsia scores, irrespective of H. pylori status.38 One large study suggested that S. boulardii increased eradication rates as a consequence of reduced side effects improved compliance and completion of therapy (with identical eradication rates on a per-protocol analysis).39 The supplementation with S. boulardii is associated with no additional side effects, demonstrating its safety.40
Despite the increase in eradication rates when S. boulardii is added to standard triple therapy, it has been shown that standard amoxicillin-clarithromycin-based triple therapy plus S. boulardii still has worse results in terms of eradication rates than probiotic-free levofloxacin-based triple or sequential therapies.41
Although trials comparing different probiotics are rare, one such study found that the supplementation of triple therapy with L. rhamnosus, with lactobacilli plus bifidobacteria, or with S. boulardii all resulted in identically lowered incidences of diarrhea and dysgeusia compared with the placebo group, with no effects on compliance or eradication rates.42
One final group of studies has looked at more heterogenous preparations of probiotics. A randomized comparison of standard triple therapy with kefir (a fermented milk-based product) compared with triple therapy plus a milk-based placebo found an increased eradication rate with kefir, with a decrease in the frequency and severity of side effects.17 A previous systematic review of 10 randomized trials analyzing the addition of fermented milk-based probiotic preparations to eradication protocols had found a benefit for the treatment group in eradication rates by intention-to-treat analysis, although with a heterogenous effect in the reduction of treatment-related adverse events.43
A trial of standard triple therapy with a multistrain yogurt preparation containing L. acidophilus, L. casei, B. longum, and S. thermophilus found comparable eradication rates to the control group by intention-to-treat analysis, but higher rates by per-protocol analysis. Contrary to all other studies, the frequency of side effects was higher in the yogurt group, while the severity was identical in both groups.44 The addition of a similar yogurt preparation to second-line moxifloxacin-amoxicillin-based therapy did not affect either eradication rates or the incidence of side effects.45
The data presented above justify the need for a new meta-analysis, as has been performed by Wang et al46 in the present issue of this journal, and which addresses the limitation of the use of different probiotic formulations by the different trials, by including only those studies using probiotic preparations containing both lactobacilli and bifidobacteria. This combination not only approximates commercially available foodstuffs, including yogurts, but has also been associated with a wider number of trials and with less contradictory results, as shown above. Moreover, as unsuccessful eradication is a problem for both first-line and second-line therapies, the inclusion of both types of study in the present meta-analysis overcomes what can be perceived as a limitation of previous meta-analyses,46 which focused solely on first-line eradication, whereas it is patients in second-line therapy who probably will benefit more from adjuncts to therapy, because of their primary refractoriness.
The authors found that preparations containing both lactobacilli and bifidobacteria were able to improve eradication rates and decrease the incidence of side effects in adults regardless of ethnicity and independently of the eradication protocol used.46 The putative relationship between improved tolerance, increased compliance, and eradication success was, however, not analyzed; therefore the question remains whether there is a direct effect of this combination of probiotics on H. pylori, or whether the benefit is a consequence of the ability to complete treatment as planned.
Considering that the risk-benefit ratio is positive because of their favorable safety profiles,47 the final decision to add a probiotic to eradication therapy should weigh the clinical trial results against patient-specific aspects. It has previously been suggested that the usefulness of probiotic adjunct therapy is particularly relevant in patients with a history of gastrointestinal intolerance to antibiotic treatment.25 Other factors to take into account should include patient preference (including a taste for yogurt, kefir, or other fermented milk products) and the probability that supplementation in capsule form could lead to decreased compliance due to the greater number of daily pills to ingest or to a cumbersome treatment protocol that is incompatible with the patient’s lifestyle. The additional cost to therapy should also be discussed with the patient and analyzed against the loss of productivity or of work hours because of treatment-associated side effects, most notably diarrhea and epigastric discomfort.
One final aspect to weigh into the clinical decision are the results currently obtained with sequential therapy, with improved tolerability due to the shorter course of the individual antibiotics, and with eradication rates of over 92% with first-line therapy and over 97% after second-line rescue, which are higher than those reported for probiotic-supplemented standard triple therapy.48
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