Abstract
Preliminary evidence has suggested that probiotics may improve eradication rates in patients infected with Helicobacter pylori treated by triple therapy. This study examined the effect of combining triple therapy with kefir, a fermented milk drink containing probiotics. A randomized, double-blind study was carried out on 82 consecutive patients with symptoms of dyspepsia and H. pylori infection confirmed by the urea breath test. Patients were given a two times a day, 14-day course of lansoprazole (30 mg), amoxicillin (1,000 mg), and clarithromycin (500 mg) with either 250 mL of kefir twice daily (triple therapy + kefir, n = 46) or 250 mL of milk containing placebo (triple therapy + placebo, n = 36). Side effects were determined using a standard questionnaire form at 15 days after beginning treatment. Patients returned for urea breath tests 45 days after beginning treatment. Significantly more triple therapy + kefir patients achieved eradication (36 of 46 [78.2%]) compared with triple therapy + placebo patients (18 of 36 [50.0%]) (P = .026, χ2 test). Side effects were significantly less frequent and less severe in triple therapy + kefir patients than in triple therapy + placebo patients. We conclude that a 14-day regimen of triple therapy with kefir is more effective in achieving H. pylori eradication than is triple therapy alone.
Introduction
T
Mounting evidence has suggested that probiotics are beneficial in a range of different gastrointestinal conditions. 7,8 Probiotics are live microorganisms that when administered in adequate amounts confer a health benefit on the host and include Streptococcus thermophilus, Enterococcus species, Saccharomyces species, and various species of lactobacilli and bifidobacteria. 9 Although the administration of probiotics alone does not seem to be sufficient to eradicate H. pylori, 10 some 11,12 but not all 13 –16 studies have suggested that probiotics supplementation to triple therapy may increase the eradication rates. Additionally, there is evidence to suggest that probiotics may reduce the side effects of triple therapy. 13,14
Kefir is a probiotic mixture prepared by culturing fresh or pasteurized milk with kefir grains containing lactobacilli, lactic streptococci, yeasts, and acetic acid bacteria. 17 Although several studies have suggested that kefir may be beneficial for lactose intolerance and other intestinal diseases, 7,18 there has been no formal prospective work to look for any positive contribution that kefir might give to eradication rates and tolerability profile of triple therapy for H. pylori eradication. Here we sought to address this issue in a randomized, double-blind, single-center study of patients from Turkey.
Subjects and Methods
Patients
This randomized, double-blind, single-center study involved 82 patients with dyspepsia enrolled at the Department of Gastroenterology, Uludag University School of Medicine, Bursa, Turkey. The hospital is a referral health care institution and has a high clinical complexity. For the purpose of this study, kefir was prepared at the Microbiology Laboratory of EKER Corp. (Bursa, Turkey).
Dyspepsia symptoms included epigastric pain or discomfort, nausea, vomiting, eructation, bloating, or heartburn. Prestudy H. pylori infection was detected in all patients by the urea breath test methodology using a single breath sample collected by straw 30 minutes post-ingestion of [ 14 C]urea. Patients were excluded if they were under 18 years of age, had concurrent esophagitis, gastric ulcer, prepyloric ulcer, pyloric channel ulcer, duodenal ulcer, or pyloric stenosis, or were receiving concurrent treatment with proton pump inhibitors, antibiotics, antibacterials, bismuth-containing compounds, or other drugs that could potentially interact with triple therapy. No patient consumed kefir before starting the study.
Patients were randomized to receive a two times a day, 14-day course of lansoprazole (30 mg), amoxicillin (1000 mg), and clarithromycin (500 mg) with either 250 mL of kefir twice daily (triple therapy + kefir, n = 46) or 250 mL of milk containing placebo (triple therapy + placebo, n = 36). The randomization code was not broken for data analysis until the database for the study had been authorized and closed. All patients gave their informed consent to be included in the study, which was conducted in accordance with the Declaration of Helsinki and was approved by our local ethics committee.
Follow-up
Periodic follow-up visits were planned on days 15 and 45 after beginning treatment. Side effects (diarrhea, abdominal pain, dyspepsia, taste impairment, fever, skin rash, nausea, vomiting, and anorexia) were assessed by questionnaire at day 15 using a 4-point Likert scale (1 = no side effects, 2 = mild side effects, daily activities were not affected; 3 = moderate side effects, daily activities sporadically affected; and 4 = severe side effects requiring treatment to be stopped). H. pylori status was assessed by the urea breath test 45 days after beginning treatment.
Data analysis
Groups were compared on baseline variables by χ2 and Student's t tests. For comparison of eradication rates and side effects, the χ2 test was applied. SPSS for Windows (version 17.0, SPSS Inc., Chicago, IL, USA) was used to perform all analyses. Tests were two-sided and done at the .05 significance level.
Results
Patient population
A total of 82 patients were enrolled. Of these, 46 patients were enrolled in the triple therapy + kefir group (26 men and 20 women; mean age, 46 ± 12 years) and 36 in the triple therapy + placebo group (20 men and 16 women; mean age, 43 ± 12 years). H. pylori was diagnosed using [ 14 C]urea breath testing in all participants. Age (P = .26) and gender (P = .93) were similar in the two groups. There were also no statistically significant differences (P = .98) in cigarette smoking prevalence between the triple therapy + kefir (nine of 46, 19.5%) and triple therapy + placebo (seven of 36, 19.4%) groups.
H. pylori eradication rates
The eradication rates were 78.2% (36 of 46) in the triple therapy + kefir group and 50.0% (18 of 36) in the triple therapy + placebo group, which was statistically significant (P = .026).
Adverse events
Table 1 shows common adverse events in the two study groups. The occurrence of diarrhea (relative risk = 0.48; P = .001), headache (relative risk = 0.17; P = .008), nausea (relative risk = 0.47; P = .029), and abdominal pain (relative risk = 0.38; P < .001) was significantly lower in the triple therapy + kefir group than in the triple therapy + placebo group. However, most adverse events were mild to moderate in intensity (Table 2). Diarrhea, headache, nausea, and abdominal pain were less prevalent and milder in the triple therapy + kefir group.
CI, confidence interval; NS, not significant; RR, relative risk.
*P < .05, **P < .01 versus triple therapy + placebo.
Discussion
In the present study, we have shown that triple therapy with adjunctive kefir increases H. pylori eradication rates and has a positive impact on H. pylori triple therapy-related adverse effects in dyspeptic patients.
Because current triple therapy for H. pylori infection is frequently associated with resistance to antibiotics, 19 there has been much interest in alternative treatment methods (including probiotics) to control H. pylori infection. Although Oh et al. 20 initially suggested that probiotics may produce soluble factors capable of killing H. pylori, these findings were not subsequently confirmed by Wendakoon et al. 10 However, the same research group has suggested that probiotics—although not sufficient for eradicating the infection—may be very effective in the inhibition of H. pylori growth. 10 In clinical studies, the addition of probiotics in the form of yogurt has been proved to be successful in reducing H. pylori eradication rates in some 11,12 but not all 13 –16 studies. Kefir contains several major strains of bacteria not commonly found in yogurt, including Lactobacillus caucasus, Leuconostoc spp., Acetobacter spp., and Streptococcus spp. 21,22 Although in this study we did not directly compared the effects of kefir and yogurt on H. pylori eradication rates, further research aiming to compare kefir with other fermented dairy products is warranted to address this issue.
An interesting finding of our study is that diarrhea, headache, nausea, and abdominal pain were less prevalent and milder in patients who received kefir plus triple therapy. There is evidence to suggest that probiotics may have a positive impact on H. pylori therapy-related adverse effects, 13,14 and data from meta-analysis have shown that the frequency of diarrhea associated with triple therapy is reduced when probiotics are added. 23 The reduction in adverse effects as observed in our study following kefir addition may have important implications for compliance of triple therapy.
Our pilot results must be considered within the context of study limitations. The number of patients in each treatment arm was relatively small. Only patients of Turkish descent were enrolled in this study. Data suggest that treatment regimens for H. pylori from industrialized countries may not necessarily be translatable to the developing world. 12 In addition, we did not know the exact amount and distribution of probiotics in the kefir consumed. Finally, our study cannot address the important mechanistic question concerning the mechanisms of the observed effect of kefir on the tolerability of standard triple therapy. However, the clinically important, statistically significant observation made in this study may stimulate further research in the field.
In summary, this study is the first to report that the addition of kefir to triple therapy increased H. pylori eradication rates and decreased triple therapy-related adverse effects. Our findings suggest that the addition of kefir into triple therapy might be an option to increase its tolerability profile and the H. pylori eradication rate. These results firmly support the previous observation on the potential usefulness of fermented milk-based probiotic preparations for the improvement of H. pylori eradication protocols. 24 –26
Footnotes
Acknowledgment
The authors are grateful to EKER Corp. (Bursa, Turkey) for the gift of the kefir used in this study.
Author Disclosure Statement
No competing financial interests exist.
