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Volume 10 • Number 2 • 2005
H E L I C O B A C T E R
Efficacy of Cranberry Juice on Helicobacter pylori Infection:
a Double-Blind, Randomized Placebo-Controlled Trial
Lian Zhang,* Junling Ma,* Kaifeng Pan,* Vay Liang W. Go,† Junshi Chen‡ and Wei-cheng You* *School of Oncology, Peking University, Beijing Institute for Cancer Research, China; †David Geffen School of Medicine at UCLA, USA; ‡International Life Sciences Institute (ILSI) Focal Point in China, China A B S T R A C T
Background. Helicobacter pylori infection is a major
Results. A total of 189 subjects with positive 13C-urea
cause of peptic ulcer disease and gastric cancer. This breath test results prior to randomization completed study postulated that cranberry juice would be effective the study. At day 35 of intervention, 14 of the 97 in the suppression of H. pylori in an endemically (14.43%) from the the cranberry juice treatment group infected population at high risk for gastric cancer.
and 5 of the 92 (5.44%) of the placebo recipients had Materials and methods. A prospective, randomized,
negative 13C-urea breath test results. After 90 days, double-blind, placebo-controlled trial was conducted the study concluded that 14 of the 97 subjects in the in Linqu County of Shandong Province, China, cranberry juice treatment group versus 5 of the 92 in where 189 adults aged 48.9 ± 11.2 years (mean ± SD) the placebo group yielded negative test results. Eleven with H. pylori infection were randomly divided individuals from the cranberry juice treatment group into two groups: cranberry juice (n = 97) and placebo and only two from the placebo group were negative (n = 92). Participants were assigned to orally receive at 35 and 90 days of experiment. These results are two 250-ml juice boxes of cranberry juice or matching placebo beverage daily for 90 days. The degree of Conclusions. Regular consumption of cranberry
H. pylori infection was determined using the 13C-urea juice can suppress H. pylori infection in endemically breath test before randomization at 35 and 90 days of intervention to assess the efficacy of cranberry juice Keywords. Intervention, Helicobacter pylori, cran-
Helicobacter pylori infection occurs world- was introduced as a new treatment modality as wide, but the prevalence rate among adults well as rescue treatment for antibiotic-resistant in developing countries is over 80%, whereas strains of H. pylori [9–10]. Although most of it falls between 20% and 50% in industrialized these therapeutic modalities are effective, they countries [1]. Accumulated evidence obtained are usually associated with mild to moderate, or in Linqu County, Shandong Province of China even severe, adverse effects [8–10]. Furthermore, indicates that H. pylori infection is associated it is very costly and controversial to apply these with an increased risk of developing gastric forms of therapy to populations with endemic cancer [2–4], one of the most prevalent diseases H. pylori infection. Thus, an alternative mode of treatment, particularly of nontoxic, natural The first line regimen for eradication of products, that proves more cost-effective and H. pylori infection currently includes a triple applicable to affected populations without evok- therapy, which combines two known antibiotics ing the side effects of antimicrobial treatments, with a proton pump inhibitor [6–7]. However, because triple therapy fails to eradicate infection It has been suggested that cranberry juice pre- in 10–20% of patients [8], quadruple therapy vents urinary tract bacterial infection in femalepatients [11–15]. Although the potential mechan- Reprint requests to: Dr Wei-cheng You, School of isms of action are unclear, in vivo and in vitro Oncology, Peking University, Beijing Institute for studies have illustrated that cranberry juice can Cancer Research, 52 Fu-cheng Road, Hai-dian District, help avoid infection by preventing Escherichia Beijing 100036, People’s Republic of China. E-mail:[email protected] coli bacteria from adhering to the uroepithelium 2005 Blackwell Publishing Ltd, Helicobacter, 10, 139– 145
[16]. Bacterial adherence to mucosal cells is the Institute Review Board (IRB) of the School of initial step in the development of urinary tract Oncology approved the study protocol in April infections. Inhibition of H. pylori adhesion to 2002, and the study was completed in December the human gastric mucosa by a high-molecular- 2002. Three hundred eighty six adults from Linqu weight constituent of cranberry juice was recently County ranging from 26 to 64 years of age were demonstrated in vitro [17]. Based on this and invited to participate in the study. After the names other evidence that cranberry juice possesses of all participants were transcribed from village beneficial health effects, the present randomized, population rosters, health officials (Drs L. Zhang double-blind, placebo-controlled trial was designed and J. Ma) visited each individual to detail the and carried out to investigate whether cranberry study and offer consent forms to those interested.
juice would suppress H. pylori in an adult Individuals who agreed to participate provided signed consent and proceeded to take a 13C-urea Province. Information regarding the population, breath test. No current information on the par- gastric cancer deaths, and prevalence of H. pylori ticipant’s drinking or smoking habits was collected.
infection in Linqu County are described in the However, according to a previous case-controlled study of gastric cancer, most residents of LinquCounty were tea drinkers, and approximately81% of the men and 5% of the women were cigarette smokers [18–19]. None of the subjectshad received treatment with antibiotics prior to their participation in this study. The flow of par- This randomized, double-blind, placebo-controlled ticipants through this trial is illustrated in Fig. 1.
trial was conducted in an adult population inLinqu County under the supervision of thefaculty from Peking University School of Oncology and in accordance with the principles Two hundred fifty-five adult subjects produced set forth in the Declaration of Helsinki. The positive 13C-urea breath tests and progressed 2005 Blackwell Publishing Ltd, Helicobacter, 10, 139– 145
Cranberry Juice for H. pylori Infection through the intervention trial. All subjects wererandomized to receive 90-day treatment with two 250 ml doses of either cranberry juice or The primary outcome of the study is based on placebo daily. The look-alike placebo beverage the number of subjects whose initial positive contained vitamin C, sugar and natural cranberry 13C-urea breath test results were negative at flavoring and coloring to simulate the taste of the 35 and 90 days study. Sample size calculations cranberry juice. Ocean Spray, Inc. [Middleboro, were performed before the trial began. Investiga- Massachusetts, USA] provided both the cranberry tors assumed that the overall rate of reduction juice and placebo beverage. Trained field staff in H. pylori infection that could be attributed interviewed all subjects according to a structured to cranberry juice was 20%, with corresponding questionnaire that included age, sex, address, power (β) = .80, two-sided α = .05, and a sample occupation, previous history of peptic ulcers, and size of 69 subjects in each of the two groups.
whether any medications, antibiotics, or both were To account for the possibility of subjects lost taken during the study. Cases of the beverage to follow-up, the actual sample size power was were distributed to participants every 12 days.
increased to include 30–40% more subjects than Treatment compliance was confirmed by a daily the calculated sample size. Eradication rates of beverage box count. Dietary information was H. pylori in the cranberry and placebo groups obtained from the subjects’ accomplished ques- were compared, and statistical differences were tionnaire. To maintain high compliance, staff determined using a two-tailed χ2 test at α = .05 members from the Peking University School of Oncology visited the participants in their homesand counted the empty boxes every 3–5 days.
Empty boxes were collected during each new distribution of beverage supply. Compliance Ocean Spray Cranberries, Inc., sponsor of this was calculated based on any remaining beverage intervention trial, made the double-blind, placebo- in the returned packaging. Poor compliance controlled approach possible. They provided the means that the subject did not drink the cranberry cranberry juice used in the experimental arm of juice or placebo continuously in 5 days. The the study and the look-alike beverage that served subjects with poor compliance were excluded from the study. All field and laboratory proce-dures were performed double-blind. Because the 13C-urea breath test is generally considered to bethe gold standard clinical, noninvasive test for A total of 225 subjects were initially enrolled in detecting active H. pylori infection [22–24], it the study, as depicted in the trial profile (Fig. 1).
was used in this study to determine the efficacy One hundred eighty-nine subjects completed of this potential treatment modality.
the study, from which 36 withdrew or were After randomization, H. pylori infection status excluded because they disliked the taste of the in each subject was evaluated using 13C-urea cranberry or placebo beverage and failed to breath test at 35 and 90 days of intervention to provide sample for the 35- or 90-day 13C-urea assess the effectiveness of the treatment. Subjects breath test, or had poor compliance during the fasted overnight before undergoing the breath progress of the study. The data presented are test, and baseline samples of exhaled CO were from the 189 subjects who completed the trial collected the following morning. Each subject and provided initial 13C-urea breath test values was then requested to drink 20 ml of water and along with values at 35 and 90 days.
ingest 80 mg 13C-urea (> 99%), and their exhaled Satisfactory treatment balance within strata CO was collected in sampling tubes 20 and defined by baseline data was achieved through 30 minutes later. 13CO values were determined randomization. Demographic details, including using gas isotopic ratio mass spectrometer (GIRMS), gender, age, and occupation of participants from and any concentration of 13CO at 20 or 30 minutes both groups, are shown in Table 1. Participants’ that exceeded the baseline concentration more age ranged from 26 to 64 and the trial was than 4 parts per 1000 (> 0.4%) was regarded as balanced accordingly into two groups by gender positive [23]. In our previous studies, the sensi- and occupation as well. There were no differ- tivity and specificity of this test were 94% and ences between the questionnaires presented to 83%, respectively, in this population [25,26].
the cranberry and the control groups. Figure 2 2005 Blackwell Publishing Ltd, Helicobacter, 10, 139– 145
Demographics of the participants of the study Classification of individuals according to Helicobacter pylori status, as measured by the 13C-urea breath test, and percentage of those who moved from H. pylori- *At both 35 and 90 days, the individuals consuming cranberry juice had agreater chance of moving from an H. pylori-positive to -negative (–) thanthe individuals consuming placebo (χ2 = 4.23; p = .04). The critical value, breath test value is independent of juice type was rejected.
δ = delta over baseline value of 13C-urea breath test. of adults are infected with H. pylori [27]. In an Profile of the participants’ compliance to the trial, early factorial trial of three interventions to reduce both in the cranberry juice treatment group and the control the progression of precancerous gastric lesions in Linqu, 35 among 1142 subjects receiving a illustrates the compliance of the subjects. Over 2-week course treatment with amoxicillin and the 90-day trial, the overall average compliance omeprazole developed rashes, from which six rate among cranberry treatment and placebo discontinued treatment because of adverse reac- tions [28]. Through this randomized, double- At day 35 and day 90, results of the breath blind, placebo-controlled study in Linqu, we test for H. pylori were negative in 14 of the 97 observed that cranberry juice can retard H. pylori infection in humans and may be a promising new juice and five of the 92 (5.44%) who consumed form of therapy for worldwide management of placebo (Table 2). Among 14 negative subjects in this infection that does not induce the side- the treatment group, 11 subjects were negative effects caused by antibiotics. Furthermore, because at 35 and 90 days, whereas only two of same sub- the prevalence rate of H. pylori infection is 72% jects were negative both at 35 and 90 days from in the Linqu adult population, the 14% reduc- the placebo group. We further calculated the tion in the infection rate observed in this trial means of delta over baseline values of 13C-urea may significantly decrease the spread of infec- breath test at 35 and 90 days from the treatment tion and risk of gastric cancer, although the mode and placebo groups. Although the means of delta of transmission of H. pylori in humans is yet over baseline value was significantly reduced to 1.97 at 90 days as compared with 2.52 before the Cranberry Vaccinium macrocarpon is a natural treatment among 97 subjects in the cranberry fruit, and this study is a testimony to what has group (p < .05). However, no statistical differ- not been previously reported – that dietary con- ence was found between the values at 35 days sumption of cranberry juice can partially suppress (2.11) and 90 days (1.97) in this group. Again, we H. pylori infection in humans. Cranberries are found the difference of means of delta over base- native to North America and are extensively line value was not statistically significant at cultivated for commercial use in certain states, 35 days (0.11) and 90 days (0.16) among 11 H. including Wisconsin, Massachusetts, New Jersey, pylori-negative subjects from the treatment group.
Oregon, and Washington [26]. Cranberry juicecocktail is considered to be effective in prevent-ing or treating urinary tract infections because Discussion
of its ability to prevent bacterial adhesion to the In Linqu County, a rural area in China with one lining of the urinary tract. This bacteriostatic of the world’s highest prevalence rates of gastric property of cranberry juice has been attributed cancer, 52% of children aged 3–4 years and 72% to proanthocyanidins [30]. In addition, it is a 2005 Blackwell Publishing Ltd, Helicobacter, 10, 139– 145
Cranberry Juice for H. pylori Infection good source of vitamin C, fructose, and bio- of cranberry juice may be the result of other flavonoids with antioxidant properties, which phytonutrients present in the juice. Recently, may also contribute to the bacteriostatic effect it has been shown that the anthocyanins, pro- of its juice. Recent work by Burger et al.
anthocyanidins, and flavonol glycosides in reveals that a high molecular weight constituent cranberry extract have antiproliferative and syn- of cranberry juice can inhibit H. pylori adhesion ergistic effects on human tumor cell lines [39].
to the human gastric mucosa in vitro [17,31].
These phytonutrient components of the cranberry This high molecular weight constituent acts on and their possible role in H. pylori infection sialyllactose-specific adhesins of H. pylori and may also affect other adhesins such as BabA, a In this clinical trial, the efficacy of cranberry 78-kDa outer membrane protein that binds to juice on H. pylori infection at 35 days was similar the fucosylated Lewis B blood group antigen to that at 90 days of intervention. However, the [32]. Based on animal model studies, BabA is density and intensity of bacteria in the gastric relevant in H. pylori-associated diseases and may mucosa of the 13C-urea-positive subjects were influence disease severity [33]. The 3′sialyllactose unknown. A mild degree of H. pylori coloniza- sodium salt, an ant adhesion oligosaccharide tion in the gastric mucosa may cause increased sensitivity to cranberry juice treatment because was recently used in a double-blind, placebo- the infection is less extensive and the gastritis controlled clinical study to treat H. pylori is nonatrophic in general [40]. As the effects of infection [34]. The ant adhesive therapy was safe cranberry juice cocktail on H. pylori infection and well tolerated, but did not suppress or were already apparent at day 35 of this trial, it cure H. pylori colonization in humans [34]. In is suggested that future intervention studies use contrast, Xiao and Shi have recently demon- this as the outcome endpoint or longer. Further- strated that cranberry juice fed to mice infected more, investigations among selected populations with H. pylori can clear H. pylori at a rate of 80%, that include children and teenagers are needed 24 hours after the treatment, and at an eradication to assess the efficacy of cranberry juice in delay- rate of 20%, 4 weeks following treatment [35].
ing or preventing H. pylori infection early in life.
We did not study the efficacy of cranberry juice cranberry juice affects H. pylori colonization and on H. pylori infection in children who appear to suppression warrants further investigation.
be more susceptible to the infection than adults A few studies suggested that vitamin C may [27], but the current results may have implica- play a role in H. pylori infection. Park et al.
tions for prevention of the infection with safety management and preventive measures during between vitamin C levels in whole blood, plasma childhood. Murry et al. have reported an inverse and gastric juice and the severity of H. pylori relationship between alcohol consumption and infection in 452 Korean children [36]. Simon H. pylori infection, in which modest consumption et al. have indicated that higher serum levels of of wine and beer prevents infection presumably ascorbic acid were associated with a decreased through the suppression of the bacterium [41].
seroprevalence of H. pylori and of pathogenic On the other hand, smoking and coffee con- cag A+ strain of H. pylori among White Amer- sumption have been found to be unrelated to icans [37]. Furthermore, Jarosz [38] investigated active H. pylori infection [41]. These findings the effects of 5 g of vitamin C daily for 4 weeks encourage further investigation alongside the in the treatment of H. pylori infection among the necessary studies that are aimed at elucidating patients with dyspeptic symptoms and chronic the dose–response relationship and mechanisms gastritis, their results suggest a 30% eradication of action of the phytonutrients present in cran- of the infection. The preparation of placebo in this study did involve vitamin C, and this may In conclusion, this is the first human interven- be the reason why five subjects from the placebo tion trial, to our knowledge, designed to study group who originally tested positive for H. pylori the effects of cranberry juice on H. pylori later tested negative. The cranberry juice and infection. The results of this preliminary study placebo contained 37.5 mg/100 ml of vitamin C; in Linqu County suggest that regular consump- therefore, each subject had a daily intake of tion of cranberry juice may reduce H. pylori 188 mg of vitamin C per day, a far lower dose infection in adults, which remains an important than previously discussed. However, the effects 2005 Blackwell Publishing Ltd, Helicobacter, 10, 139– 145
This study was supported by a grant from Ocean 12 Henig YS, Leahy MM. Cranberry juice and Spray Cranberries, Inc. The authors thank Dr Joseph urinary tract health: science supports folklore.
Speroni and Daisy Hong from Ocean Spray, Inc. for their excellent technical assistance, and Debra A.
13 Stothers L. A randomized trial to evaluate effec- Wong from the University of California, Los Angeles tiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against uri-nary tract infection in women. Can J Urol2002;9:1558–62.
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