Is There a Role for Probiotics in Helicobacter pyloriTherapy?

The role of probiotics in Helicobacter pylori therapy remains unclear. Lactobacilli can be shown to inhibit H pylori in vitro. Some strains of Lactobacilli may exert specific antimicrobial effects. There is no strong evidence of a benefit on eradication rate when probiotics are added to a regimen. Despite promising results obtained using compounds of L reuteri and S boulardii , high-quality trials are needed to define the role of probiotics as adjuvant therapy. Variables that remain to be studied with L reuteri , currently the most promising strain, include dosage, frequency of administration, administration in relation to meals, and duration of therapy.

Key points

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Probiotics are live bacteria that may confer a health benefit to the host.
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Several studies provided evidence that probiotics may also compete directly with Helicobacter pylori , interfering with other pathogens colonization or by the production of antimicrobial molecules.
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The effectiveness of many commonly recommended treatments has declined to unacceptably low levels for the increasing antimicrobial resistance and compliance reduction.
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Lactobacillus reuteri has been shown to inhibit H pylori in vitro and in vivo and may play a role in eradication therapy.
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The goals of this therapy could be to eradicate H pylori , reduce the inflammation associated with the infection, and enhance therapy by improving treatment success.

What probiotics are

Microbial communities are present on all mucosal surfaces. The intestinal tract is the host to a vast microbe community that plays an important role in the integrity and function of the gastrointestinal tract. They also provide a relevant contribution in the maturation and induction of gut-associated lymphoid system (innate immunity), and stimulation of specific systemic and local immune responses (acquired immunity). The gut-associated lymphoid system is a major component of the immune system, accounting for more than 70% of lymphoid tissue.

In addition, the gut microbiome consumes, stores, and redistributes energy allowing humans to extract calories from otherwise indigestible carbohydrates. In humans, the contribution of microbial fermentation to the host’s energy balance is usually around 10% to 30%. Short chain fatty acids promote colonocyte proliferation, acidification of the intracolonic environment, enhancement of colonic contraction, stimulation of colonic blood flow, and absorption of salt and water. Moreover, these microbial communities serve as an important barrier against pathogen colonization by competing for attachment sites and for available nutrients, as well as by directly inhibiting pathogen growth by altering the intraluminal pH, reducing redox potential, and producing inhibitory molecules such as bacteriocins. Disturbances of the intestinal epithelial barrier function can result in increased uptake of microbial and food antigens, stimulating the mucosal immune system and triggering an inflammatory response.

However, the gut microbiome also has the potential to contribute to the development of diseases by a variety of mechanisms. Conditions affecting gastric acid barrier, such as use of antisecretory drugs, gastric atrophy, surgery, autoimmune disease, and aging, or local mucosal and systemic immune diseases, such as selective immunoglobulin A deficit, human immunodeficiency virus infection, immunosenescence, and/or intestinal clearance modifications may result in qualitative and quantitative alterations of gastric, digiuno-ileal, and colonic flora dysbiosis (ie, specific bacteria overgrowth/reduction).

What probiotics are

Microbial communities are present on all mucosal surfaces. The intestinal tract is the host to a vast microbe community that plays an important role in the integrity and function of the gastrointestinal tract. They also provide a relevant contribution in the maturation and induction of gut-associated lymphoid system (innate immunity), and stimulation of specific systemic and local immune responses (acquired immunity). The gut-associated lymphoid system is a major component of the immune system, accounting for more than 70% of lymphoid tissue.

In addition, the gut microbiome consumes, stores, and redistributes energy allowing humans to extract calories from otherwise indigestible carbohydrates. In humans, the contribution of microbial fermentation to the host’s energy balance is usually around 10% to 30%. Short chain fatty acids promote colonocyte proliferation, acidification of the intracolonic environment, enhancement of colonic contraction, stimulation of colonic blood flow, and absorption of salt and water. Moreover, these microbial communities serve as an important barrier against pathogen colonization by competing for attachment sites and for available nutrients, as well as by directly inhibiting pathogen growth by altering the intraluminal pH, reducing redox potential, and producing inhibitory molecules such as bacteriocins. Disturbances of the intestinal epithelial barrier function can result in increased uptake of microbial and food antigens, stimulating the mucosal immune system and triggering an inflammatory response.

However, the gut microbiome also has the potential to contribute to the development of diseases by a variety of mechanisms. Conditions affecting gastric acid barrier, such as use of antisecretory drugs, gastric atrophy, surgery, autoimmune disease, and aging, or local mucosal and systemic immune diseases, such as selective immunoglobulin A deficit, human immunodeficiency virus infection, immunosenescence, and/or intestinal clearance modifications may result in qualitative and quantitative alterations of gastric, digiuno-ileal, and colonic flora dysbiosis (ie, specific bacteria overgrowth/reduction).

Probiotics

The role for intestinal microbes in health and disease has been recognized in alternative and complementary forms of medicine for many years. The Russian Nobel Prize recipient Eli Metchnikoff, professor at the Pasteur Institute in Paris, in 1907 states that “senility is due to poisoning of the body by the products of certain of these intestinal bacteria…. The multiplication of these organisms could be prevented by a diet containing milk fermented by bacilli which produce large amounts of lactic acid.”

Manipulation of the intestinal microflora with therapeutic intention is the subject of intensive and ongoing research. The methods by which the intestinal microflora can be altered include administration of antibiotics, prebiotics (dietary components able to promote the growth and metabolic activity of beneficial bacteria), and probiotics. Probiotics are microorganisms that have beneficial properties for the host. This definition has been made more precise over time. For example, Fuller described probiotics as “live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance”. He stressed 2 important factors: the viable nature of probiotics and the capacity to help with intestinal balance. In 2001, an Expert Consultation of international scientists working on behalf of the Food and Agriculture Organization of the United Nations and the World Health Organization defined probiotics as, “live microorganisms which when administered in adequate amounts confer a health benefit on the host”. The International Scientific Association for Probiotics and Prebiotics organized a meeting of clinical and scientific experts on probiotics (with specialties in gastroenterology, pediatrics, family medicine, gut microbiome, microbiology of probiotic bacteria, microbial genetics, immunology, and food science) in 2013 to reexamine the concept of probiotics and suggested a more grammatically correct definition: “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.” Overall, the definition includes the essence of the term, microbial , namely, viable and beneficial to health.

The European Commission advised the Food Safety Authority of Ireland that where terms like ‘live’ or ‘active’ are used to describe bacteria and imply a probiotic function, they are considered to be health claims. Because no health claims have been approved for ‘probiotic,’ terms that imply a probiotic function are not permitted. For this reason, currently any terms that imply probiotic activity (ie, imply that the bacteria in the product may be beneficial for health) are considered health claims and are thus not permitted.

In contrast, in Italy there is a long tradition of consuming “beneficial bacteria” administered as food supplements or food ingredients. Their use in the food sector has been under the regulation of the Italian Ministry of Health for more than 13 years. Recently, the use of the word probiotic for food and food supplements was updated, requiring certain conditions, including a minimum number of viable cells (1 × 10 ⁹colony-forming unit [CFU]) administered per day, a full genetic characterization of the probiotic strain, and a demonstrable history of safe use in the Italian market.

Sardinia, a Mediterranean Italian island, is the site of a hot spot of exceptional longevity, called the Longevity Blue Zone, located on the mountain. This observation has stimulated a strong interest in traditional food as one of the potential causal factors of the exceptional longevity. It has been shown that consumption of dairy products, both from goats and sheep, especially a sort of fresh sour cheese called casuajedu , which is rich in Lactobacilli , was abundant in this region. Another important source of Lactobacilli in this special Sardinian population is a bread prepared from whole grains with ‘homemade’ microbial starters. It has been demonstrated that this type of bread is associated with a reduction in postprandial glucose and insulin blood levels of up to 25% compared with regular bread and thus is potentially able to preserve the function of pancreatic insulin-secreting cells and prevent obesity and diabetes.

Use of Probiotics Clinically

The complexity of the microbial community is not yet completely understood; however, there is strong scientific interest in proving the benefits of probiotics in the therapeutic armamentarium. The available literature includes well-designed clinical trials, systematic reviews, and metaanalyses ascribing beneficial medical effects with several well-studied probiotic microbial species.

The list of these microorganisms includes strains of lactic acid bacilli such as Lactobacillus and Bifidobacterium , a nonpathogenic strain of Escherichia coli, “ E coli Nissle 1917,” Clostridium butyricum, Streptococcus salivarius , and Saccharomyces boulardii , a nonpathogenic strain of yeast. There are also strains that have been genetically engineered to have specific properties, such as to stimulate secretion of specific cytokines and thus to modulate the immune system.

Specific probiotic species, alone or in combination, have suggested potential efficacy in several gastrointestinal illnesses. The best studied to date include inflammatory bowel diseases, antibiotic-related diarrhea, Clostridium difficile colitis, infectious diarrhea, hepatic encephalopathy, irritable bowel syndrome, and allergy. Therapeutic benefit has also been suggested in several other disorders including the use of probiotics in the treatment of Helicobacter pylori infection.

Probiotics as adjuvant therapy for Helicobacter pylori eradication

In recent years the use of probiotics as adjuvant therapies in H pylori eradication has been extensively studied and its role is still debated. The Maastricht IV guidelines emphasize that certain prebiotics and probiotics show promising results as an adjuvant treatment in reducing side effects (evidence level 5, grade of recommendation D).

Lactoferrin has been used to improve H pylori treatment. Two metaanalyses obtained the same results and showed that lactoferrin increases the efficacy of proton pump inhibitors and clarithromycin-containing triple therapies. However, the poor quality of many trials and the limited number of centers involved should be emphasized and preclude giving a positive recommendation.

Metaanalyses on the studies where Lactobacilli were used are heterogeneous, because they mixed different species and strains. For this reason, additional work needs to be performed to determine the strain, dose and administration to be used. A metaanalysis on the use of S boulardii as adjuvant to triple therapy showed not conclusive results.

All these treatments are most likely to lead to a decrease of adverse events, especially diarrhea, and only indirectly may help to improve the eradication rate by an improvement in the compliance.

Recently, O’Connor and associates observed that some probiotics, such as Lactobacilli and Bifidobacteria , exert an anti– H pylori effect in vitro and were helpful in reducing antibiotic-related side effects. The most frequently studied agents have been Lactobacillus sp. strains. In 1 study where 70 naıve patients were treated, Lactobacillus reuteri increased eradication rate by 8.6% and reduced the reported side effects when compared with placebo-supplemented triple therapy. A metaanalysis of 9 studies on probiotic use as an adjunct to triple therapy found that when specific Lactobacillus strains were used, eradication rates increased significantly by 17%, but when multistrain probiotics were used, eradication rates enhanced by only 2.8%. This also was reflected in 2 other trials from Iran and Brazil where multistrain probiotics as adjunct therapy failed to show a benefit for eradication.

Bifidobacterium infantis has also been proposed as having anti– H pylori activity, and in a recent study from Asia, it was observed that adding it to standard triple therapy increased the cure rate from 69% to 83% and when pretreatment with 2 weeks of B infantis was given as well, the success rate of eradication increased to 91%.

If eradication regimens take into account local and regional resistance patterns and use optimized acid suppressant therapy, adjunct probiotic therapy seems add little to treatment efficacy. In scenarios characterized by low H pylori eradication rates, the addition of L reuteri may lead to a therapeutic gain of 10%. The strength of probiotics as add-on therapy, however, is their ability to reduce antibiotic side effects and thereby improve adherence.

In contrast, Navarro-Rodriguez and colleagues concluded that the use of probiotic compound ( Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifido bacterium , and Streptococcus faecium ) compared with placebo in the regimen in Brazilian patients with peptic ulcer or functional dyspepsia showed no difference in efficacy or adverse effects rate. In this double-blind study, patients with peptic ulcer or functional dyspepsia infected by H pylori were randomized to receive a triple therapy with furazolidone, tetracycline, and lansoprazole regimen twice a day for 7 days. Patients received placebo or a probiotic compound in capsules twice a day for 30 days. A symptoms questionnaire was administered at baseline, after completion of antibiotic therapy, after the probiotic, use and 8 weeks after the end of the treatment. Upper digestive endoscopy, histologic assessment, rapid urease test, and breath test were performed before and 8 weeks after eradication treatment. One hundred seven patients were enrolled: 21 men with active probiotic and 19 with placebo plus 34 women with active probiotic and 33 with placebo for a total of 55 patients receiving active probiotic and 52 receiving placebo. The per protocol (PP) eradication rate with active probiotic was 89.8% and with placebo 85.1% ( P = .49); intention to treat 81.8% and 79.6%, respectively ( P = .53). The rate of adverse effects at 7 days with the active probiotic was 59.3% and 71.2% with placebo ( P = .20). At 30 days, it was 44.9% and 60.4%, respectively ( P = .08).

Four recent meta-analyses have tried to better clarify the role of probiotics in the treatment of H pylori infection. Szajewska and colleagues selected 5 randomized, controlled trials comparing Saccaromyces boulardii given along with triple therapy compared with placebo or no intervention. They found that S boulardii significantly increased the eradication rate with a relative risk [RR] of 1.13 (95% CI, 1.05–1.21) and reduced the risk of overall related adverse effects with a RR of 0.46 (95% CI, 0.3–0.7), especially with regard to diarrhea (RR, 0.47; 95% CI, 0.32–0.69).

Wang and colleagues performed a metaanalysis of 10 clinical trials. They included all parallel controlled trials comparing Lactobacillus -containing and Bifidobacterium- containing probiotic compound preparation supplementation or not during H pylori eradication therapy. Eradication odds ratio (OR) was available for 1469 patients (708 in the probiotic supplementation group and 761 in the control group). The pooled OR by intention to treat and by PP analysis in the probiotics supplementation versus no probiotics was 2.06 (95% CI, 1.40–3.06) and 2.32 (95% CI 1.72–3.14), respectively. The pooled OR of incidence of total side effects was significantly decreased in the probiotics supplementation group (OR, 0.3; 95% CI, 0.1–0.8) by the random model without significant publication bias. The authors concluded that Lactobacillus -containing and Bifidobacterium -containing probiotic compound preparation during H pylori eradication therapy in the adult may have beneficial effects on eradication rate and incidence of total side effects.

Zheng and colleagues in another metaanalysis evaluated 9 randomized, controlled trials containing Lactobacilli performed on adult and children showing a significantly increasing in the eradication rate with a RR of 1.4 (95% CI, 1.06–1.22), but without a significant decrease in overall side effects (RR, 0.88, 95% CI, 0.73–1.06).

Finally, Dang and associates included eligible randomized, controlled trials examining effects of probiotics supplementation on eradication rates and side effects, published up to May 2014. Subgroup analysis was performed to compare different probiotic strains and antibiotic therapies with different effectiveness in controls (eradication rates of 80% vs 80%). The quality of the trials was assessed with the Cochrane risk of bias tool. The pooled data suggest that supplementation with specific strains of probiotics compared with eradication therapy may be considered an option for increasing eradication rates, particularly when antibiotic therapies are relatively ineffective. The impact on side effects remains unclear and more high-quality trials on specific probiotic strains and side effects are thus needed. Table 1 summarizes the overall results.

Table 1

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