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Intern Emerg Med

DOI 10.1007/s11739-013-1013-z

IM - ORIGINAL

Lactobacillus reuteri in the treatment of Helicobacter pylori


infection
Maria Pina Dore • Marianna Cuccu •
Gianni Mario Pes • Alessandra Manca •

David Yates Graham

Received: 29 September 2013 / Accepted: 21 October 2013


Ó SIMI 2013

Abstract Probiotics have proven to be useful in the Keywords Probiotics  Lactobacillus reuteri 
treatment of a number of gastrointestinal diseases. Probi- H. pylori  Treatment
otics may compete directly with Helicobacter pylori, pos-
sibly by interference with adherence or by the production
of antimicrobial molecules. Lactobacillus reuteri has been Introduction
shown to inhibit H. pylori in vitro and in vivo, and theo-
retically may play a role in eradication therapy. The aim of Helicobacter pylori infection is etiologically involved in
this study was to examine the efficacy of L. reuteri in the gastritis-associated diseases, gastric ulcer, duodenal
H. pylori eradication therapy. This was an open label single ulcer, gastric adenocarcinoma, and primary gastric B cell
center study. H. pylori infection was defined as positive lymphoma and may play a role in some cases of non-ulcer
gastric histopathology and 13C-UBT. Intervention con- dyspepsia. Cure of H. pylori infection dramatically alters
sisted of L. reuteri (DSM 17938) 108 cfu plus pantoprazole the natural history of gastritis and its sequelae. Currently,
20 mg twice a day for 8 weeks. Eradication was defined as antibiotics in combination with antisecretory therapy are
a negative 13C-UBT, 4–6 weeks post therapy. Compliance the standard of care for patients with H. pylori infections.
was considered good if at least 90 % of the total number of However, increasing antimicrobial resistance has made
the pills were taken. 21 of 22 subjects completed the study successful treatment of H. pylori infections a challenge as
without protocol violation (mean age 52 years; 36 % men). the effectiveness of many commonly recommended treat-
L. reuteri plus pantoprazole twice a day cured 13.6 % (3/ ments has declined to unacceptably low levels [1, 2].
22; 95 % CI 2.9–34.9 %) of patients with H. pylori Newer regimens have improved treatment success, how-
infection by ITT analysis and 14.2 % (3/21; 95 % CI ever, the widespread occurrence of the infection in many
3.0–36 %) by PP analysis. Overall urease activity assessed countries and the need of two or three antimicrobials
before and 4–6 weeks post therapy showed a significant suggest that antimicrobial resistance may soon undermine
reduction with a difference of mean of 38.8 vs. 25.4 by these currently more successful combinations [3].
one-tailed test (P = 0.002). In conclusion, L. reuteri may The clinical manifestations of infectious diseases typi-
have a potential role in H. pylori eradication therapy if the cally represent an interaction between the infecting
cure rate can be improved by changes in dose, dosing microbe and the host, both of which may influence the
interval, or duration of therapy. outcome [4]. Normally, the local microbiome provides a
stable environment that resists colonization by pathogens.
To understand, and to enhance the ability to manipulate,
M. P. Dore (&)  M. Cuccu  G. M. Pes  A. Manca
Dipartimento di Medicina Clinica e Sperimentale, the normal microbiome with therapeutic intention is an
Clinica Medica, University of Sassari, area of active research. Probiotics are live bacteria that may
Viale San Pietro 8, 07100 Sassari, Italy confer a health benefit to the host [5]. In the early 20th
e-mail: mpdore@uniss.it
century, the Russian Nobel laureate Élie Metchnikoff [6]
M. P. Dore  D. Y. Graham suggested the possibility of colonizing the gut with bene-
Baylor College of Medicine, Houston, TX, USA ficial flora. Currently Lactobacillus and Bifidus spp. are the

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Intern Emerg Med

most common microbes used as probiotics in the gastro- UBT. Post-treatment success was defined by a negative
13
intestinal tract [7, 8]. C-UBT 30–40 days after completing therapy.
Probiotics have been used in the therapy of H. pylori
13
infection, and have proven useful in reducing side effects C-Urea breath test
of traditional antimicrobial therapy and for enhancing
patients’ compliance [9]. Some strains of L. reuteri have The 13C-UBT was performed according to a standardized
previously been shown to prevent the early stage of protocol, the sensitivity and specificity of which have been
H. pylori colonization in the human gastrointestinal tract, reported to be of 95 % [14]. All breath tests were analyzed
possibly by inhibition of H. pylori binding to putative at the same laboratory using a single gas isotope ratio mass
glycolipid receptor molecules [10]. Colonization has been spectrometer (ABCA, Europe Scientific, Crewe, UK).
associated with alterations of the immune response of the
gastrointestinal mucosa [11]. Importantly, L. reuteri has Medication
also been shown to produce an antimicrobial compound,
3-hydroxy propionaldehyde (reuterin), which is a broad The intervention consisted of L. reuteri (DSM 17938,
spectrum antibiotic against Gram negative and positive ReuflorÒ, BioGaia AB, Sweden) 108 cfu/tablet plus pan-
bacteria including H. pylori [12, 13]. toprazole 20 mg twice a day. The cfu declared contained
This was a pilot study to investigate the efficacy of per tablet was confirmed in two different labs (Sassari and
L. reuteri for the treatment of human H. pylori infection. Houston). The choice of the probiotic was based on the
previous anecdotal experience. No treatment was admin-
istered thereafter. The L. reuteri was administered fasting
Methods at least 2–3 h before the mid-day and evening meals.
Pantoprazole 20 mg was given just before breakfast and
Patients dinner. All drugs were given for 60 days. The duration of
treatment chosen for the study was arbitrary. The cost of
This study was a prospective, single center, open label pilot the drugs used for treatment (pantoprazole plus L. reuteri
study. Patients scheduled for upper endoscopy for any tablet) was € 141.66.
reason and found to be positive for H. pylori infection were
invited to enter. Patient compliance

Exclusion criteria The patients were evaluated by a physician for compliance


and side effects after completing treatment and at follow-
Exclusion included: severe gastritis (mucosa intensively up by direct questioning. Side effects including diarrhea,
hyperemic, granular and fragile, easily bleeding by the nausea, vomiting, stomach ache, taste disturbance, dizzi-
scope touch), peptic ulcer, pregnancy or lactation; malig- ness, headache, skin rash, constipation and lack of appetite;
nancy, severe liver, heart, kidney or endocrine diseases or were graded as mild (did not limit daily activities), mod-
any other clinically significant medical condition, alcohol erate (limited daily activities to some extent), or severe
abuse, drug addiction, or a history of allergy to pantop- (made daily activities all but impossible), and recorded.
razole or L. reuteri. Patients who received bismuth com-
pounds, antisecretory drugs, or antibiotics during the Study design and statistical analysis
4 weeks before endoscopy were also excluded.
Written informed consent was obtained from all par- A two-stage design was applied. In the two-stage design
ticipants, and the study was approved by the local ethics the patients are divided into two groups. At the completion
committee. There was no pharmaceutical company partic- of the first stage, an interim analysis is made to determine if
ipation in any phase of the study. the second stage should be conducted (e.g., a stopping rule
is utilized). If the number of patients responding is greater
Definition of H. pylori infection than a certain amount, the second stage will be con-
ducted—otherwise, not. The optimal two-stage design to
Two biopsy specimens were taken from the antrum, one test the null hypothesis that P B 0.200 versus the alterna-
from the angulus, and two from the gastric corpus for tive P C 0.350 has an expected sample size of 36 and a
histology to assess the presence of H. pylori. H. pylori probability of early termination of 0.630. After testing the
infection was defined as the presence of typical histology therapy on 20 patients in the first stage, the trial would be
and bacteria on histologic examination of the gastric terminated if four or fewer responded and the details would
biopsies stained by H&E and GIEMSA and a positive 13C- be reconsidered (e.g., dose, dosing interval etc.). If more

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Intern Emerg Med

than four were cured, a total of 62 patients would be therapy showed a significant reduction with a difference of
studied. If the total number cured was less than or equal to means of 38.8 vs. 25.4 by one-tailed test (P = 0.002)
17, the drug would be rejected. Analysis of H. pylori (Fig. 1). Treatment failures by L. reuteri-based therapy
eradication efficacy was performed on an intention-to-treat were, subsequently, cured with bismuth-based quadruple
(ITT) basis including all eligible patients enrolled in the therapy twice a day [15].
study, and on a per-protocol (PP) basis excluding patients
lost to the follow-up and protocol violations. Patient compliance and side effects

Overall tolerability was good. Excellent compliance


Results (100 %) was achieved in all cases. Data on side effects
were available for all 21 treated patients. No patient
A total of 22 consecutive patients fulfilling the inclusion complained of side effects.
criteria were enrolled in stage 1 (19 women, median age
51 years, range 21–68 years). All subjects had experienced
dyspeptic symptoms. The enrollment stopped after the first Discussion
stage according to the study design (four or fewer patients
responded to the treatment). No patient had peptic ulcer Lactobacillus species are rod-shaped Gram positive bac-
disease, gastric or duodenal erosions. Twenty-two patients teria able to produce lactic acid leading to the micro-
took the medications as prescribed and H. pylori eradica- environment acidification [16]. Lactobacillus spp. have the
tion status was assessed after treatment. One patient was capacity to colonize the gastric mucosa [17] and the lactic
dropped from the study because he received antibiotics for
pneumonia. None were lost to the follow-up (Table 1). Table 1 Intervention status of patients enrolled in the study
Status Patients
H. pylori eradication
Received intervention 22
21 patients completed the study with one protocol viola- Drop-out 1
tion. Twelve patients were treatment naive for H. pylori Lost to follow-up 0
infection and nine patients had previous H. pylori treat- Completed trial 21
ments that failed to cure the infection. L. reuteri plus Intervention ineffective 18
pantoprazole twice a day cured 13.6 % (3/22; 95 % CI Cure rate ITT 14 % (3/22)
2.9–34.9 %) of patients with H. pylori infection by ITT 95 % CI 2.9–34.9
analysis and 14.2 % (3/21; 95 % CI 3.0–36 %) by PP Cure rate PP 14 % (3/21)
analysis (Table 1). The cured patients included one patient 95 % CI 3.0–36
with a history of several previous unsuccessfully therapies. ITT intention-to-treat analysis, PP per-protocol analysis, CI confi-
Overall urease activity assessed before and 4–6 weeks post dence interval

Fig. 1 Difference in urease 120


activity assessed before and I 13C-UBT II 13C-UBT
4–6 weeks post therapy by 13C-
urea breath test (UBT) 100
Delta 13C- UBT Value

80

60

40

20

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Patient number

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Intern Emerg Med

acid produced by Lactobacilli has been shown to inhibit the LC-1 does not improve the antibiotic effect [27]. In an
growth of H. pylori at concentrations of 50–156 mmol/L uncontrolled study, Michetti et al. [28] report a decrease in
[18]. Pre-treatment of rats with L. rhamnosus GG at urease activity as assessed by UBT in 80 % of patients
109 cfu/mL twice daily for three consecutive days mark- positive for H. pylori infection treated for 2 weeks with
edly reduced the ethanol-induced mucosal lesion area by 50 mL of L. johnsonii (La1) supernatant combined with
45 %, and significantly increased the basal mucosal pros- either omeprazole 20 mg four times a day or with placebo.
taglandin E(2) and PGE(2) levels suggesting that a local In accordance with these results a decrease in urease
gastroprotective action may also be present [19]. L. gasseri activity of 76 % was also observed in our patients. How-
in rat models also enhanced gastric ulcer healing of acetic ever, our study did not assess H. pylori urease activity or H.
acid-induced gastric ulcer [20]. These studies show a pylori density and our assessment was done at least
potential beneficial effect of Lactobacilli in the stomach. 4 weeks after stopping therapy, a time lapse that should
In a study from Japan, administration of L. reuteri strain have allowed any direct effect to have dissipated. Sub-
ATCC 55730, four times daily for 8 weeks significantly sequent studies are needed to assess the mechanism and
decreases 13C-UBT delta levels in H. pylori positive sub- whether the effect was L. reuteri related. In addition, we
jects, demonstrating a suppression of H. pylori urease cannot exclude that such a phenomenon depends on the
activity and H. pylori density. H. pylori density was 60-day pantoprazole therapy itself. Because this was an
investigated on the base of cfu obtained from the biopsy open label study, the absence of a control group with
gastric cultured mucosa. Patients were divided in a low pantoprazole without L. reuteri prevents any definite con-
density (\1 9 105 cfu/mL), moderate density (between clusion. An open label crossover study in 31 H. pylori
1 9 105 and 5 9 105 cfu/mL), and high-density group positive Japanese subjects reports a slight, but significant
(5 9 105 cfu/mL). The individual UBTs were then corre- decrease (Excess 13CO2 (%0); 26.6 ± 13.7 vs.
lated to the established H. pylori quantity [21]. In a study 20.9 ± 11.8; P \ 0.05), in urease activity following con-
from Italy, patients were assigned to receive standard 7-day sumption of 90 g of yogurt containing L. gasseri (LG 21)
triple without or with L. reuteri supplementation; or a twice a day for 8 weeks [29]. Other studies have reported
7-day triple therapy with a probiotic mixture; or a 14-day beneficial effects of Lactobacillus strains when added to
standard triple therapy plus a probiotic mixture. Overall, H. the triple therapies against H. pylori and a meta-analysis by
pylori eradication was achieved in up to 80 % of patients. Wang et al. [30] on the efficacy and safety of Lactobacillus
A statistically significant difference among the different and Bifidobacterium-containing probiotic compound prep-
regimens (range 53–71 %) was not reported [22]. Despite aration in H. pylori eradication therapy, report an overall
this result other studies have demonstrated that Lactobacilli beneficial effects of probiotics. Eradication odds ratio
can produce beneficial effects [23–25]. The beneficial (OR), was available for 1469 patients (10 trials; 708 in the
effects described for Lactobacillus strains include being probiotics supplementation group and 761 in the control
able to stabilize the mucosal barrier by increasing mucin group). The pooled OR by ITT analysis and by PP analysis
expression, reducing bacterial overgrowth, stimulating in the probiotics supplementation over without probiotics
mucosal immunity and synthesizing antioxidant substances was 2.066 (95 % CI 1.398–3.055) and 2.321 (95 % CI
[25]. Lactic acid producing bacteria also generate a variety 1.715–3.142) in each group except in patients accepting
of metabolic products that are capable of interfering with rescue therapy, and in children. The incidence of total side
the growth of other microbes [26]. However, none of these effects is significantly decreased in the probiotics supple-
observations alone or together have prompted the use of mentation group (OR = 0.305; 95 % CI 0.117–0.793) [30].
Lactobacillus species to cure H. pylori infection. Subgroup analysis for Lactobacillus was not performed.
There have been a number of studies evaluating the In another study, 120 H. pylori positive patients were
probiotic effects of Lactobacillus strains in reducing anti- randomized to receive rabeprazole, clarithromycin and
microbial side effect, enhancing compliance and improving amoxicillin, either with or without a lyophilized and
the cure rate with traditional H. pylori therapies in humans inactivated culture of L. acidophilus twice daily. A sig-
[27–30]. Following a 3-week intake of 180 mL of LC-1 nificantly higher eradication rate was observed in the L.
acidified milk twice a day in a placebo-controlled study a acidophilus-supplemented group (88 %), with respect to
decrease in gastric inflammation and H. pylori density is the control group (72 %) [31]. Diarrhea, nausea and taste
reported. LC-1 acidified milk is fermented milk containing disturbance, assessed by questionnaire, were significantly
107 cfu of L. johnsonii La1 per mL (Hirz, Production Plant reduced in the Lactobacillus strain GG-supplemented
and Nestle Research Centre, Orbe, Switzerland). During group. Saggioro et al. [32] in a randomized, placebo-con-
the last 2 weeks of therapy, volunteers in both groups were trolled pilot study published as an abstract reported 30
treated with clarithromycin 500 mg twice a day. Clari- dyspeptic patients, positive for H. pylori infection by his-
thromycin eradicates H. pylori in 26 % of the subjects and tology, rapid urease test (CLO-test) and 13C-UBT who

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Intern Emerg Med

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