Diet and Helicobacter pylori infection.

Helicobacter pylori infection has accompanied man for thousands of years. In some infected patients, a complex and dynamic pathogen-host reaction triggers pathogenic pathways resulting in development, inter alia, of atrophic gastritis, peptic ulcer disease (both gastric and duodenal), gastric adenocarcinoma, and MALT lymphoma. Large-scale eradication therapy is associated with a rapid increase in antibiotic resistance, gut flora composition disturbances, and increased risk of development, inter alia, of paediatric infectious diarrhoeas, atopic diseases, and oesophageal adenocarcinoma. Our diet contains many substances with potent antibacterial activity against H. pylori. Dietary interventions enable a decrease in H. pylori colonisation and result in a decrease in gastritis prevalence, thus potentially lowering the risk of gastric adenocarcinoma development.

Introduction

Despite the fact that research on Helicobacter pylori and its role in pathogenesis of gastric and duodenal diseases was initially conducted in the second half of the 19th century, scientific breakthroughs were not observed until the 1980s. At that time, Robin Warren and Barry Marshall from the University of Perth published in Lancet the results of their studies on so-called Campylobacter-like organisms (CLOs) and their association with gastritis. The actual amount of publications makes Helicobacter pylori the second, after Escherichia coli, most commonly studied and described pathogen [1].

Helicobacter pylori (Campylobacterales order) is a helical, Gram-negative bacillus that colonises the human’s oral cavity and stomach. In developing countries, the rate of colonised subjects amounts to 70–80%, whereas in developed countries this rate is approximately 13% to 50% of the population [2].

Diseases associated with Helicobacter pylori infection

In the majority of patients, H. pylori infection is asymptomatic, in the form of mild gastritis without hydrochloric acid secretion disorders. The ulcerative phenotype of H. pylori infection, observed in 15–20% of infected persons, is associated with an increased inflammation of pre-pyloric stomach, hypergastrinaemia, increased hydrochloric acid secretion, and peptic ulcers (both gastric and duodenal). The gastric cancer phenotype of H. pylori infection, observed in approximately 1% of infected persons, is characterised by an increased inflammation within the gastric corpus, mucous membrane atrophy in pre-pyloric stomach, decreased hydrochloric acid secretion, and significantly increased risk of gastric cancer development [3]. Indications for eradication therapy, apart from gastric cancer and peptic ulcer disease, are as follows: MALT lymphoma, atrophic gastritis, dyspepsia, immune thrombocytopenia, iron deficiency anaemia of unknown origin, B12 vitamin deficiency and previous treatment of gastric cancer or MALT lymphoma, as well as family history of those malignancies. Moreover, eradication therapy can be realised on the patient’s request [4].

In recent years, a potential role of H. pylori infection in the development of, inter alia, non-alcoholic steatohepatitis, insulin resistance, type 2 diabetes mellitus, colon adenomas and adenocarcinoma, bile ducts cancer, dementia, psoriasis, and chronic utricaria has also been recognised [5, 6].

Eradication therapy

Pharmacological therapy of Helicobacter pylori infection is based on at least two antibiotics combined with a double dose of proton-pump inhibitor (PPI). The estimated efficacy of this therapy is 82% (triple regimen) to 92% (sequential therapy). New therapeutic regimens, containing fluoroquinolones (levofloxacin and moxifloxacin), exhibit high efficacy (85% and 90%, respectively) and good safety profile, but their use is limited by high costs [7]. The problem of eradication therapy is the abruptly increasing resistance of H. pylori to the most commonly used antibiotics. Moreover, eradication therapy requires multiple-day complex drug administration and is associated with side effects, mainly gastrointestinal (e.g. diarrhoea, nausea, and taste disturbances), which can lead to treatment discontinuation. In addition to antibiotic resistance, it is believed that lack of observance to doctor’s prescriptions is the main cause of eradication failure.

Long-term antibiotic treatment results in qualitative and quantitative modification of gut flora, selection of resistant strains of H. pylori and other intestinal bacteria, enhances colonisation of GI tract by Candida fungi, and can lead to severe Clostridium difficile infection [8].

Helicobacter pylori has accompanied man for at least 58,000 years [9]. More and more data indicates that bacterial colonisation, as well as long-term negative consequences, may also provide some benefits to the host. It is known that H. pylori infection can mitigate the course of infection with other more virulent intestinal pathogens, e.g. Vibrio cholerae [10] and may protect against diarrhoeagenic gastrointestinal infections in children [11]. Reports on atopic asthma and other atopic diseases prevalence reduction in the H. pylori-infected population as well as on the reduction of coeliac disease, irritable bowel syndrome (IBS), gastro-oesophageal reflux disease (GORD), and oesophageal adenocarcinoma frequency were also published [12].

An eradication therapy has been known for last few decades. Long-term disruptions of long-lasting association between pathogen and host as well as ‘profit and loss account’ for normal population are difficult to predict.

Alternative methods of Helicobacter pylori infection treatment

In light of the above considerations, questions concerning the potential association between complete eradication and H. pylori infection-associated disease reduction as well as the link between reduction of colonisation with methods other than antibiotics and potential achievement of predefined goals, especially gastric cancer development reduction, seem to be of key importance. The main studies on alternative therapies include substances of plant origin, probiotics, peptides, and polysaccharides [13]. Although alternative therapies do not allow for permanent H. pylori eradication, they reduce bacterial colonisation, the degree of stomach inflammation, and mucosal atrophy [14, 15]. Some methods enhance the efficacy of traditional antibiotic treatment and simultaneously prevent antibiotic side effects [16-18].

In this paper, I have focused on readily available food products with proven bacteriostatic or bactericidal properties against H. pylori, highlighting those in which its anti-H. pylori effectiveness in vivo was confirmed in humans. Relatively low cost, overall availability, and lack of side effects are the main advantages of such methods.

Lactoferrin

Lactoferrin is a glycoprotein of the transferrin family, exhibiting antibacterial properties. It chelates iron ions, and thus limits the availability of this element to bacteria. Lactoferrin is present in mothers’ and cow’s milk, neutrophils’ granules, saliva, and tears. It is an element of non-specific immunity.

In their study, Wang et al. demonstrated in a mouse model that lactoferrin decreased bacterial colonisation and H. pylori-induced gastritis [14]. In a meta-analysis of prospective randomised trials assessing the impact of lactoferrin addition to triple or quadruple eradication regimens, lactoferrin significantly increased the rate of effective eradications and decreased side effect severity [16]. Beside a reduction in the availability of iron ions, lactoferrin may exhibit synergistic effects with antibiotics due to facilitation of their penetration through the cell membrane.

Isothiocyanates

In traditional medicine, sauerkraut juice has been considered as an efficacious remedy for peptic ulcer disease for centuries. Brassica vegetables (among others cauliflower, swede, headed cabbage, rape, radish) contain substances called isothiocyanates. The above-mentioned substances exhibit anti-cancer activity, such as: apoptosis induction, inhibition of cellular proliferation, and modulation of liver cytochromes involved in carcinogen metabolism. In a prospective trial involving approximately 18,000 Chinese patients, an association between the risk of malignancy occurrence, inter alia, gastric cancer, and urine isothiocyanate metabolite concentration was assessed. During the 16-year observation concerning a group of patients with high levels of urine isothiocyanates metabolites, the risk of gastric cancer occurrence was lower. This effect was independent of the body mass index (BMI) value; however, it was not observed in smokers and patients with regular alcohol intake. The authors believe that the protective effect of isothiocyanates should be attributable, inter alia, to their bactericidal activity against H. pylori [19].

Sulforaphane, the highest concentrations of which (in the form of a precursor called glucoraphanin) are observed in broccolis and their sprouts, is one of the isothiocyanates inhibiting growth of H. pylori. Sulforaphane also exhibits in vitro bactericidal activity against H. pylori (MIC – 2 µg/ml), including clarithromycin-resistant strains [20]. In the study by Yanaka et al. involving asymptomatic patients with confirmed H. pylori infection, a broccoli sprout intake of 70 g/day (containing 420 µmol of glucoraphanin) resulted in significant decrease of colonisation intensity, which was assessed in urea breath test and H. pylori antigen stool test. This therapy was well tolerated, and no adverse effects associated with broccoli sprouts intake were reported [21].

Phenolic derivatives

Many fruits exhibit in vitro bacteriostatic activity against H. pylori. It is believed that the antibacterial activity of fruit extracts results from their content of phenolic derivatives [22]. Highbush blueberry extract exhibits in vitro activity reducing H. pylori adhesion to mucous, erythrocytes, and gastric epithelial cell culture. In their study, Chatterjee et al. proved that raspberry, strawberry, blackberry, and bilberry extracts demonstrate potent bacteriostatic activity against clarithromycin-resistant H. pylori strains [23].

Zhang et al. conducted a prospective randomised double-blinded trial involving 189 adults with H. pylori infection, who were drinking 250 ml of blueberry juice during a 90-day period. In 14.46% of patients, urea breath test was negative on the 35th day. The above-mentioned effect was also maintained on the 90th day [24].

Honeys

Antibacterial activity of honeys is attributable, inter alia, to their high osmolarity, and low pH and hydrogen peroxide content. Some types of honeys, such as oak tree and manuka honeys, exhibit potent in vitro bacteriostatic activity against H. pylori and inhibit urease activity. In the study assessing nutrition habits of 150 patients with dyspepsia, honey intake at least once a week was associated with significantly lower prevalence of H. pylori infection [25].

Oils and fatty acids

In 1994, Thompson et al. demonstrated that polyunsaturated fatty acids, omega-3 and -6, inhibit in vitro growth of H. pylori [26]. Moreover, oils of plant origin contain many polyphenols exhibiting bacteriostatic activity against H. pylori. In laboratory conditions, the following food products exhibit bacteriostatic activity against H. pylori: blackcurrant seed oil, fish oil, carrot seed, or grapefruit seed oils [27].

In their prospective trial, Castro et al. demonstrated the bacteriostatic activity of olive oil [28], whereas Ito et al. in their Japanese study indicated that polyunsaturated fatty acids intake decreases the prevalence of atrophic gastritis [15].

Probiotics

Certain probiotic strains exhibit antibacterial activity resulting from, inter alia, their capability to modify immunologic response of the host, secreting antibacterial substances such as lactic acid and disturbing bacterial adherence mechanisms [29].

A systematic review of five randomised controlled trials demonstrated that the addition of Sacharomyces boulardii to the triple H. pylori eradication therapy was associated with increased eradication rate and diminished incidence of gastrointestinal side effects [17]. In the study by Armuzzi et al., supplementation of Lactobacillus GG along with triple therapy did not affect the eradication rate but was associated with reduction of treatment-related side effects [18].

A number of diet components have been shown to have potential anti-H. pylori activity in in vitro and animal models.

Thus far, the outcomes in human trials have been mixed. Garlic, vitamin C and E, green tea, red wine, and liquorice have been most commonly investigated as potential therapeutic agents [13]. Further well-designed clinical trials are required to determine their effectiveness in affected populations, as a treatment option and preventive measure.

Summary

The understanding of the mechanisms and factors determining asymptomatic and symptomatic course of H. pylori infection and its long-term effects is the key to selection of patients with potential benefit from eradication therapy. Treatment of all H. pylori colonised populations seems to be less probable and could be potentially associated with negative effects within asymptomatic carriers. Currently, the agents used in eradication regimens are associated with many negative effects, including rapidly increasing antibiotic resistance.

The possibility of H. pylori infection treatment with food products seems to be a very attractive option due to relatively low cost, availability, and lack of adverse effects. At present, most of the data confirms the antibacterial activity of broccoli sprouts, highbush blueberry juice, and some types of plant oils. Keenan et al. [30] obtained promising results from their studies assessing in vitro effect of the combined use of different substances of plant origin with established anti-H. pylori activity. A synergistic effect, inter alia, of broccoli sprout extract and blackcurrant seed oil was demonstrated. Despite the fact that many studies confirm the antibacterial activity of substances contained in food products, the low number of prospective randomised trials assessing their use in clinical practice is striking. Lack of patentability and failure in achievement of permanent eradication, seen in previous studies, are the potential reasons for the above described situation. However, from the population’s health perspective, reduction of H. pylori colonisation intensity without the use of antibiotic treatment seems to be a promising alternative.