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- Patients and methods
According to the North American Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines,1 one-week triple therapy represents the current most widely used first-line regimen for Helicobacter pylori infection, but the eradication failure rate is more than 30%.2 Today, bacterial resistance and side-effect occurrence represent the second most frequent cause for anti-H. pylori treatment failure in clinical practise.3 Indeed, the high prevalence of antibiotic side-effects might induce even motivated dyspeptic patients to discontinue therapy, with a consequent treatment failure as well as a possible development of antibiotic-resistant strains.4 These manifestations have been related to the quantitative and qualitative changes in the intestinal microflora because of unabsorbed or secreted antibiotics in the intestinal content which results in a reduction of normal saprophytic flora, bacterial overgrowth and the persistence of potentially pathogenic antibiotic resistant indigenous strains.5
A strategy targeted to improve the treatment tolerability might increase compliance and eventually raise eradication rate. The use of probiotics has recently been proposed in adults to increase patient tolerability by limiting side-effects of eradicating therapies;4, 6–9 nonetheless, the report from the Maastricht 2000 consensus conference on H. pylori include probiotics as possible useful ‘side tools’ for management of the infection.10
Lactobacillus reuteri is a heterofermentative bacterium that resides in the gastrointestinal tract of humans and animals11 and is considered to be one of the few true autochthonous Lactobacillus species in humans.12L. reuteri has been shown to exert a beneficial effect in the prevention and treatment of several intestinal conditions.13
The demonstration that L. reuteri colonizes the stomach and duodenum combined with recent data that L. reuteri ATCC 55730 is a potent inhibitor of H. pylori growth14 prompted our study in children.
We investigated, for the first time in a paediatric population, in a double-blind, randomized, placebo-controlled trial the effect of L. reuteri on antibiotic-associated side-effects during and after H. pylori eradication therapy.
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- Patients and methods
In this randomized, placebo-controlled study, children on H. pylori eradication therapy receiving L. reuteri when compared with peers receiving placebo, reported a significant reduction of the total symptom score, which takes into account both the frequency and the severity of the symptoms. Symptoms which were most positively influenced by L. reuteri were abdominal distension, disorders of defecation, epigastric pain, eructation and halitosis.
The onset of side-effects during anti-H. pylori therapy is mainly due to the use of antibiotics in moderate to high-dose or in combination.6 Antibiotic-related side-effects are common and usually affect the gastrointestinal system. The intestinal microbiota is characterized by a high bacterial concentration, up to 1014 CFU/mL in the colon; these bacteria and colonic mucosal cells coexist in a delicate equilibrium that can be easily altered by antibacterial drugs causing the emergence of potentially pathogen species over the saprophytic flora. Unfortunately, the most frequently used antibiotics for H. pylori eradication (amoxycillin, clarithromycin, metronidazole) are frequently accompanied by gastrointestinal side-effects and clarithromycin in particular, determines an increased contractility of gastrointestinal smooth muscle, leading to accelerated transit with diarrhoea.20
Probiotics are ‘living micro-organisms which upon ingestion in certain numbers favourably influence the health of the host by improving the indigenous microbiota’.21 Many studies have documented the effectiveness of prophylactic probiotics taken with antibiotics in preventing or lowering the antibiotic-related gastrointestinal side-effect burden.22–24 It is up to the experts in microbiology, nutritional sciences and food technology to formulate unequivocal requirements for probiotic bacterial strains: bile and acid resistance, adhesion to the mucosa and/or to enterocytes, at least temporary colonization of the human gut, ability to inhibit known gut pathogens and antimicrobial substances, stability and activity during manufacture and storage, safety in human use and proven health-promoting effects.25L. reuteri shares most of these general characteristics.12, 26–29
Our choice to use L. reuteri ATCC 55730 derives from different observations. L. reuteri has been extensively studied and is widely used as a food additive to improve human gastrointestinal health.26 Oral administration delivers L. reuteri ATCC 55730 to the gastrointestinal tract, leading to the shedding of live bacteria in the faeces.27, 28 Clinical trials have shown that L. reuteri ATCC 55730 administration is safe both in adults28, 29 and in children,30 significantly reduces the incidence and the severity of diarrhoea of different origins and reduces gastrointestinal illness and infections.27, 31 Being acid resistant, they persist in the stomach longer than other bacteria surviving in high proportions (>80%) in the gastric environment for periods of 2 h.32L. reuteri ATCC 55730 adhere to gastric epithelial cells in vitro32 and recently Vauler N, et al. have shown that after its administration to healthy volunteers, it was possible to detect this strain adhering to epithelial cells from corpus and antral gastric biopsies providing the first clear and direct evidence of colonization of the human stomach by L. reuteri.14
Our experience in children on eradication therapy showed that L. reuteri is effective in reducing the total symptom score and the onset of bloating, disorders of defecation and halitosis similarly to adult data after the administration of a single strain of Lactobacillus GG (LGG)4 or Bacillus clausii6 or Saccharomyces boulardii or a mixture of Lactobacillus acidophilus, and Bifidobacterium lactis.7 However, what we have found more difficult to explain is the effect of L. reuteri on symptoms such as eructation and epigastric pain which are more likely related to H. pylori infection. This is not a novel finding since other authors have described a significant reduction of epigastric pain in the probiotic treated arm during H. pylori eradication7, 33 although no explanation was advocated. It is of interest a recent evidence that some L. reuteri strains were able to compete with H. pylori for the binding to its receptor on gastric epithelial cells (asialo-GM1 and sulfatide) suggesting that a binding inhibitor(s) is associated with the bacterial cell surface.34 Therefore, it is possible that the concomitant use of a probiotic along with eradication therapy may decrease more rapidly the bacterial load thus ameliorating symptoms such as epigastric pain. Indeed, we have demonstrated that L. reuteri ATCC 55730 is capable of decreasing the bacterial load when administered to untreated patients (R.F., personal unpublished data) as shown for other probiotic strains.35 Moreover, it is documented that probiotics have an anti-inflammatory effect that might contribute to reduce gastric inflammation when given to H. pylori colonized animals.36, 37 Despite the suitability of this hypothesis, caution should be used in attributing symptomatic benefits to probiotic oral therapy until the mechanistic bases of action of probiotics are fully understood.
A possible confounding factor in our study may be that all enrolled children were symptomatic, reason for which these children were tested and treated since in childhood there is no indication for either in the absence of symptoms.1 However, taking into account only the occurrence of new or aggravated symptoms during and after the eradication therapy when compared with baseline we have demonstrated the superiority of L. reuteri when compared with placebo at least for some symptoms.
Dealing with children, we always have a double aim when we decide to eradicate the H. pylori, being the elimination of the bacterium and the resolution of symptoms. Our data demonstrate that symptoms relief, although in the short term, is better achieved by the concomitant administration of L. reuteri together with antibiotics; in our experience, the use of L. reuteri does not improve the eradication rate, however, the small sample size of our series does not allow to draw firm conclusion, although in line with previous studies in adults.6, 7, 33 Finally, similar to previous experiences,6, 7, 33 the overall compliance of patients was not increased by L. reuteri, however, the treatment tolerability had significantly improved.
In Italy a box of L. reuteri costs 11.00 euros for 10 pills that makes 1.1 euro for each treatment day, therefore, its use would increase the overall costs of approximately 20 euros. Moreover, we have to consider that often, after an antibiotic treatment, symptomatic children receive a probiotic that it is usually what the family have at home and rarely one with proved efficacy for a particular indication.
In conclusion, our study shows, for the first time in the paediatric population, that probiotic supplementation, during and after a sequential treatment for H. pylori eradication, may positively affect therapy-related symptoms and overall treatment tolerance.