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SYSTEMATIC REVIEWS AND META-ANALYSESFasiha Kanwal, Section Editor

Proton Pump Inhibitor Use and the Risk of Small Intestinal BacterialOvergrowth: A Meta-analysis

WAI–KIT LO*,‡ and WALTER W. CHAN*

*Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Harvard Medical School; and ‡Department of Gastroenterology, BostonA Healthcare System, Boston, Massachusetts

BACKGROUND & AIMS: Use of proton pump inhibitors (PPIs) could predispose individuals to small intestinalbacterial overgrowth (SIBO) by altering the intraluminal environment and bacterial flora.There is controversy regarding the risk of SIBO among PPI users because of conflictingresults from prior studies. A systematic review and meta-analysis were performed toevaluate the association between PPI use and SIBO, using objective clinical outcomemeasures.

METHODS: Clinical studies comparing SIBO risk among adult users of PPIs vs nonusers were identifiedin MEDLINE/PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, andthe National Institutes of Health Clinical Trials databases through July 2012. Two reviewersindependently extracted data on study characteristics and outcomes. The primary metame-ter was the odds ratio (OR) of SIBO among PPI users vs nonusers. Subgroup analyses wereperformed to examine the influence of study characteristics, such as SIBO diagnosticmodality, on study outcome.

RESULTS: Eleven studies (n � 3134) met inclusion criteria. The pooled OR of SIBO in PPI users vsnonusers was 2.282 (95% confidence interval [CI], 1.238 – 4.205). No significant single largestudy or temporal effect was seen. Subgroup analysis revealed an association between SIBOand PPI use in studies that used duodenal or jejunal aspirate cultures to diagnose SIBO(OR, 7.587; 95% CI, 1.805–31.894), but no relationship was found between SIBO and PPI usein studies that used the glucose hydrogen breath test (OR, 1.93; 95% CI, 0.69 –5.42). Funnelplot analysis identified 4 outlying studies, indicating the possible presence of publicationbias.

CONCLUSIONS: PPI use statistically was associated with SIBO risk, but only when the diagnosis was madeby a highly accurate test (duodenal or jejunal aspirate culture). Differences in study resultscould arise from the use of different tests to diagnose SIBO.

Keywords: Hypochlorhydria; Drug; Small Bowel Flora; Reflux; Side Effect.

Proton pump inhibitors (PPIs) are frequently prescribed byboth primary care physicians and gastroenterologists for a

wide range of indications. They represent one of the highestclasses of medications in sales and prescription in the UnitedStates, both in the inpatient and outpatient settings.1–3 Food

nd Drug Administration–approved indications for PPI usenclude treatment of gastroduodenal ulcer, erosive esophagitis,astroesophageal reflux disease, gastric hypersecretory syn-romes, and part of the treatment regimen for Helicobacterylori. Its use has also been recommended in the hospital settings prophylaxis against gastrointestinal bleeding resulting fromtress ulcer formation in critically ill patients.4

Since the release of the first PPI in 1989, an increasing

number of studies have evaluated the long-term side effects of

PPI use, including small intestinal bacterial overgrowth (SIBO).SIBO is a condition in which increased bacterial load in thesmall bowel results in excessive fermentation and inflamma-tion, leading to a variety of clinical complaints including bloat-ing and diarrhea. The clinical symptoms are often accompaniedby weight loss and nutritional malabsorption, which may resultfrom cellular injury caused by enterotoxin production and

Abbreviations used in this paper: CI, confidence interval; GHBT,glucose hydrogen breath test; OR, odds ratio; PPI, proton pump inhib-itor; SIBO, small intestinal bacterial overgrowth.

© 2013 by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2012.12.011

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484 LO AND CHAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 5

bacterial adhesion.5 Chronic acid suppression and the resultantypochlorhydria associated with PPI use have been hypothe-ized to alter the intraluminal environment to promote growthf the bacterial flora in the small intestine. Several reports have

inked hypochlorhydria to increased gastric and duodenal bac-erial colonization,6 – 8 which have been shown to predispose

patients to SIBO development.9 Gastric hypochlorhydria haslso been implicated as a contributing factor in the risk ofeveloping SIBO in elderly10,11 and human immunodeficiencyirus12 patients.

In 1994, 2 initial reports were published examining thepossible association between PPI use and risk of SIBO.13,14 The2 studies used varying methodologies and design, includingdifferent diagnostic testing and criteria for SIBO. Conflictingoutcomes regarding the risk of SIBO associated with PPI useresulted from these 2 initial reports. Since then, a number ofcohort and case-controlled studies have been implemented inan attempt to clarify the magnitude and directionality of therisk,8,15–22 with varying results. The relationship between PPI useand SIBO, therefore, remains controversial and confusing forboth patients and clinicians. With the widespread use andavailability of over-the-counter PPI, a better assessment of itsside-effect profile and link to other conditions, such as SIBO, isessential.

A previously published review discussed the possible role ofPPIs as confounders in the association between SIBO and irri-table bowel syndrome.23 The objective of this meta-analysis wasto review available published peer-reviewed evidence to evaluateobjectively the relationship between PPI use and diagnosis ofSIBO.

MethodsData Sources and SearchesAn electronic search was performed using MEDLINE/

PubMed (1950 to July 2012), EMBASE (1980 to July 2012), theCochrane Central Register of Controlled Trials, and the USNational Institutes of Health Clinical Trials databases for case-control studies, cohort studies, or clinical trials of PPI use andSIBO published through July 2012. The following search termswere used as both keywords and medical subject heading terms,where applicable: proton pump inhibitor, PPI, omeprazole, lan-soprazole, pantoprazole, esomeprazole, rabeprazole, dexlanso-prazole, malabsorption syndromes, bacterial overgrowth. Nolanguage restrictions were applied.

Study SelectionThe authors independently reviewed the results of the

search strategy. The titles, abstracts, and keywords of identifiedarticles were screened for relevance and the reference lists ofthese articles were examined individually for additional perti-nent studies. To be included in this meta-analysis, studies wererequired: (1) to be randomized controlled trials, case-controlstudies, or cohort studies of SIBO risk in general adult (age �18y) PPI users vs nonusers; (2) to diagnose SIBO by one of thecurrently available clinical tests, namely small-bowel aspirateculture or breath testing; and (3) to include a non-PPI controlgroup. To minimize heterogeneity, studies that were publishedin abstract form were not included. Studies that focused exclu-sively on a specific subpopulation of patients at increased risk

for SIBO, such as patients with scleroderma or postabdominal

surgery, were excluded because some of these conditions may beeffect modifiers, thus skewing the association between PPI useand SIBO.

Data Extraction and Quality AssessmentTwo independent reviewers extracted data and assessed

the quality of the selected studies with no discrepancies. Thefollowing clinical data were identified a priori and extractedfrom each study, where possible: total number of subjects withand without SIBO off PPI; total number of subjects with andwithout SIBO on PPI; adjusted odds ratio (OR) of SIBO in PPIusers vs nonusers; geographic region of study; testing modalityto diagnose SIBO; cut-off values for hydrogen breath testing;number of subjects; mean age of subjects; and type, dose, andduration of PPI exposure. Formal methodologic quality wasassessed using the Newcastle–Ottawa Quality Assessment Scalefor nonrandomized studies.24 All included studies were rated 6to 8 of a maximum score of 9, and were of sufficient quality forinclusion in the meta-analysis.

Data Synthesis and Statistical AnalysisThe primary metameter for this study was the OR for

SIBO among PPI users vs nonusers. To quantify the variationacross studies caused by heterogeneity, the Cochran Q and I2

statistics were calculated, with a P value less than .05 for the Qstatistic or I2 greater than 20% considered significant for heter-

geneity. Potential sources for clinical heterogeneity amongtudies were specified a priori, including testing modality andtudy design, for which subgroup analyses were performed.hese subgroups were analyzed further by stratification to as-

ess for possible interactions between these factors. Because ofnticipated variability in patient population and study design,e used the DerSimonian–Laird random effects model forooled analysis with significance accepted at a P value less than

05. A one-study–removed analysis was performed on theooled data to examine the effect of single large studies. Aumulative analysis was also conducted to explore time trendsy publication year. The possibility of publication bias wasssessed with a funnel plot and adjusted with Duval andweedie25 trim-and-fill method. All analyses were conductedsing Comprehensive Meta-Analysis, version 2 (Biostat, Engle-ood, NJ). The meta-analysis was performed in accordance with

he Meta-analysis Of Observational Studies in Epidemiologyuidelines.26

ResultsStudy SelectionThe search strategy yielded 305 articles, of which 12

full-text studies were retrieved. The excluded 293 articles in-cluded duplicate citations, non–peer-reviewed abstracts, animalstudies, case reports or series, editorials, letters, reviews, andpractice guidelines. Of the 12 studies identified, 1 was excludedfor focusing on a specific subpopulation of patients with in-creased baseline risk of SIBO development27; however, the studywas small and had only 10 subjects, so its inclusion would havehad only a minimal impact on the overall pooled results. Theresulting 11 publications represented 11 discrete study cohortsthat were included in the meta-analysis. Figure 1 shows a flow

chart documenting the study selection process.

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In all, 11 study cohorts were identified that reported SIBOrisk in PPI users vs nonusers (n � 3134) (Table 1). Nine studieswere prospective cohort studies,8,13–19,21 and 2 were retrospectiveeviews.20,22 Seven studies13,16 –20,22 used a separate cohort of PPI

nonusers for comparison, whereas the remaining 4 stud-ies8,14,15,21 compared outcomes in the same cohort before andafter PPI exposure. Five studies used duodenal/jejunal aspirateculture obtained via small-bowel intubation for the diagnosis ofSIBO,8,13,15,17,20 whereas the remaining 6 studies used a varietyof breath testing, including the 14C-glycocholate breath test,14

glucose hydrogen breath test (GHBT),17,19,21,22 or lactulose hy-drogen breath test.18 One study7 used the lactulose hydrogen

reath test as an additional confirmatory test in a minority ofatients (n � 6) after diagnosis of SIBO by duodenal/jejunalspirate, and a second study15 used 14C-D-xylose breath testingor diagnosis of SIBO in addition to jejunal aspirate; these dataere omitted from analysis to prevent double counting of

ubjects. Another study22 compared test results of 4 differentcut-off thresholds for SIBO diagnosis in GHBT. Data from thecut-off threshold of either H2 greater than 20 or CH4 greaterthan 15 was used for this meta-analysis because this reflects themost commonly accepted practice in clinical SIBO testing cur-rently. The mean age of subjects across all studies was 52.4, withwomen comprising 64.3% of the total study population. Allstudies had a Newcastle–Ottawa score between 6 and 8, andwere of acceptable methodologic quality for inclusion in themeta-analysis.

Meta-analysisAcross all studies, a statistically significant level of het-

erogeneity was observed (Q test, 61.2; P � .001; I2, 83.7), whichwas likely attributable to the various testing modalities andcut-off ranges used in the diagnosis of SIBO. In the analysis ofthe primary metameter, 6 of the 11 included studies showed anincreased risk of SIBO with PPI use, as calculated from theextracted numeric data. The overall meta-analysis revealed a

Figure 1. Flow diagram depicting the search and selection process.

statistically significant increase in risk of SIBO after applying

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486 LO AND CHAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 5

the random-effects model to account for the observed hetero-geneity (OR, 2.282; 95% confidence interval [CI], 1.238 – 4.205)(Figure 2).

Additional analyses were run to exclude the role of a singlelarge study effect, assess the consistency of cumulative out-comes over time, and evaluate potential publication bias (Figure3). The one-study-removed analysis showed similar pooled out-comes without significant deviation from the overall result afterremoval of individual studies, suggesting no significant effectfrom a single large study (Figure 3A). Cumulative analysisshowed temporal progression, demonstrating a statistically sig-nificant risk of SIBO as studies were added over time (Figure3B). Potential publication bias was evaluated with a funnel plot,which showed 4 outlying studies with high standard error atthe right margin of the plot (Figure 3C). The Duval andTweedie25 trim-and-fill method was applied, resulting in 4 stud-ies being imputed with an adjusted OR of 1.440 (95% CI,0.778 –2.667), showing no relationship between risk of SIBOand PPI use after accounting for potential publication bias.

A subgroup analysis was performed to examine the effects ofSIBO testing modality, one of the presumed sources of heter-ogeneity, on the pooled results (Figure 4A). In the subgroupincluding only studies using duodenal/jejunal aspirate for SIBOdiagnosis, an increase in risk for SIBO among PPI users wasnoted (OR, 7.587; 95% CI, 1.805–31.894). Among studies usingGHBT for SIBO diagnosis, no relationship between PPI use andSIBO was seen (OR, 1.93; 95% CI, 0.69 –5.42). Further divisionof the breath-test subgroup was not possible given the presenceof only one study using the lactulose hydrogen breath test, andone study using the 14C-glycocholate breath test. Finally, whenhe Duval and Tweedie25 trim-and-fill method was applied tohe subgroup of studies using duodenal/jejunal aspirate forIBO diagnosis to account for potential publication bias, 2tudies were imputed with a resultant adjusted OR of 3.77695% CI, 1.144 –12.464).

A second subgroup analysis was performed to assess theffects of study and control group design (Figure 4B). Studiessing a self-control or pretest-posttest design, in which subjectsere tested for SIBO before and after PPI exposure, showed anssociation between SIBO and PPI use (OR, 9.607; 95% CI,.646 –56.089). On the other hand, studies using a separate

roup of PPI nonusers as controls showed no statistically sig- a

nificant risk for SIBO among PPI users (OR, 1.658; 95% CI,0.869 –3.163). Further analysis of the subgroups by stratifica-tion showed no change in the effect of SIBO testing modalityon outcome when controlling for study design. However, whencontrolling for SIBO testing modality, no difference in SIBOrisk among PPI users was seen by study design. These analysessuggest that the effect of test modality on outcome was inde-pendent of study design, but not vice versa.

Additional investigation of the effects of dose, duration, andtype of PPI exposure on SIBO diagnosis could not be assessedas a result of insufficient data. Clinical indications for SIBOtesting, such as irritable bowel syndrome, were not specified inevery study, and therefore could not be included in furtheranalysis.

DiscussionFor the primary metameter of interest, risk of SIBO

with PPI use, 11 studies were examined and evidence of in-creased risk was detected using random-effects pooled meta-analysis. Although there was significant heterogeneity in resultsamong studies, 6 of 11 included studies reported a statisticallysignificant increase in SIBO risk with PPI use. When potentialpublication bias was accounted for using the Duval andTweedie25 trim-and-fill method, the adjusted OR was no longertatistically significant. Subgroup analysis showed an associa-ion between PPI use and SIBO when the diagnosis was madeith duodenal/jejunal aspirate culture, the current gold stan-ard. This association persisted even after adjusting for poten-ial publication bias. In contrast, there was no relationship withPI use when SIBO was diagnosed by GHBT. Although sub-roup analysis by study type showed a limited association withIBO and PPI use for both self- and separately controlledtudies, there appeared to be some interaction between studyype and testing modality. A review of the studies (Table 1) alsohowed that of the 5 studies using aspirate for SIBO diagnosis,

featured separate controls, whereas of the 7 studies witheparate controls, only 3 were aspirate studies. In this case,ssociation as a result of study type may account for part of theelationship between SIBO and PPI use seen with studies using

Figure 2. Meta-analysis ofSIBO risk with PPI use.

spirate culture as the testing modality.

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This meta-analysis explored the relationship between PPI useand the risk of SIBO, an area that continues to remain contro-versial. Given the large patient population analyzed in thisstudy, we believe that it contributes significantly to scientificknowledge and clinical care of patients taking PPIs. When ahighly accurate diagnostic test (duodenal/jejunal aspirate cul-ture) was used, PPI use appeared to increase the risk of SIBO.

Figure 3. (A) One-study-re-oved analysis of SIBO risk to

ssess the single large study ef-ect. (B) Cumulative analysis ofIBO risk to assess the consis-

ency of results over time. (C)unnel plot of standard error byIBO risk.

Along with studies linking other adverse events to chronic acid S

suppression, such as pneumonia,28 bone loss,29 and entericnfections,30 these results highlight the potential toxicity ofPIs, the need for judicious application, and the importance ofedication reduction when reaching treatment goals.The disparate findings between duodenal/jejunal aspirate

ulture and GHBT studies underscore the need for a clinicallyelevant and accurate outcome measure for the diagnosis of

IBO. The current gold standard is duodenal/jejunal aspirate

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488 LO AND CHAN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 5

culture, which involves an invasive procedure such as endos-copy or fluoroscopy to intubate the small bowel to obtainduodenal/jejunal fluid. SIBO is diagnosed when bacterialcounts exceed 105 colony forming units per milliliter of fluid

spirate. Although the sensitivity and specificity of the testpproach 100%,31 practical considerations such as patient dis-omfort and expense resulted in the introduction of breathesting for SIBO diagnosis. Breath testing relies on the in-estion of a test dose of carbohydrate, which can then lead tohe release of a radioactive isotope (14C-D-xylose or 14C-

glycocholate breath tests) or hydrogen species (glucose orlactulose hydrogen breath tests) when digested by a higherload of bacterial flora in SIBO patients. Although diagnosticbreath tests for SIBO are simpler to administer, less invasive,and less costly than duodenal/jejunal aspirate culture, theyare comparatively less sensitive and specific31,32 (Table 2).Potential contributors to the low sensitivities of breath test-ing include increased conversion of hydrogen to methane bycertain gut microbes,33 recent ingestion of high-carbohydrateoods that can prolong hydrogen secretion, hyperventilation

Table 2. Sensitivity and Specificity of SIBO TestingModalities

Testing modality Sensitivity Specificity

spirate culture 100% 100%14C–D-xylose breath test 14%–95% 100%14C-glycocholate breath test 33% 76%GHBT 6%–93% 78%–100%

Lactulose hydrogen breath test 6%–68% 44%–70%

from recent exercise or pulmonary disease, increased loads oforal bacteria, short-gut syndrome, and low anaerobic bacte-rial load in the colon.34 Compounding the situation are the

ultiple thresholds of isotope, hydrogen, and methane de-ection that have been used to diagnose SIBO by breathesting. A systematic review of diagnostic testing options forIBO published in 2008 showed no clear standard or validityf any of the testing modalities across 71 peer-reviewedublications.35 The relatively poor performance and lack of

standardization of breath tests therefore have led many toquestion their validity and utility in the clinical diagnosis ofSIBO.

In this meta-analysis, the absence of a clear associationbetween PPI use and SIBO in the pooled analysis of studiesusing GHBT as a diagnostic modality may have resulted frommisclassification of SIBO diagnosis owing to its low sensitivityand variable specificity, leading to inaccurate and inconsistentoutcomes. One possible contributor to the observed inconsis-tency was the lack of a universally accepted cut-off threshold formany of the breath tests used to diagnose SIBO, even within asingle testing modality. Such inconsistency likely detracts fromthe usability of GHBT and other diagnostic breath tests forSIBO diagnosis. Our data also highlighted the possibility thatGHBT may be inadequate to accurately diagnose SIBO, espe-cially as an outcome measure in research studies. Althoughduodenal/jejunal aspirate culture remains the gold standard fordiagnosis of SIBO, its cost and invasiveness would likely pre-vent its widespread use in the clinical setting and for epidemi-ologic study. Therefore, further refinement of current breath

Figure 4. Subgroup analysesof SIBO risk with PPI use. (A)Subgroup analysis of SIBO riskwith PPI use based on SIBOtesting modality (duodenal/jeju-nal aspirate culture vs GHBT). (B)Subgroup analysis based onstudy design (pretest-posttest/self-control vs separate control).

testing modalities or development of a new, accurate, low-cost,

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and noninvasive diagnostic test for SIBO is urgently needed forboth clinical and investigative use.

The second subgroup analysis, which examined the possiblerole of study design, showed a statistically significant associa-tion between PPI use and SIBO in studies comparing the samecohort of patients before and after PPI exposure. On the otherhand, studies comparing SIBO diagnosis in separate cohorts ofpatients with and without PPI exposure showed no association.These results may reflect the underlying pathophysiology andpatient-specific nature of SIBO. Prior studies of duodenal/jejunal aspirate cultures showed that SIBO may be caused byincreased levels of regular flora or bacterial species that have notyet been identified.36,37 Indeed, the present findings support the

elief that the pathophysiology and exact bacterial compositionf SIBO may be unique for each individual, thus leading tootential inconsistent outcomes when different groups of pa-ients are compared against each other. In addition, althoughrevious studies have identified several characteristics such asge, anatomy, and motility disorders that may predispose toIBO,38 there are likely many other currently unknown factorshat contribute to the alteration in intraluminal bacterial envi-onment associated with SIBO. These undiscovered factors mayntroduce confounding to studies featuring 2 cohorts of sub-ects. Even in the case-control studies included, subjects coulde matched only by demographics or known factors associatedith SIBO, which may not be sufficient owing to the complex-

ties of SIBO pathophysiology. Therefore, subgroup analysis oftudies featuring subjects who served as their own controls, inhich the intestinal flora was most comparable and unknown

actors were least likely to contribute to the results, showed aore consistent and significant association between PPI use

nd the development of SIBO.One limitation of this study was the detection of possible

ublication bias. The funnel plot (Figure 4) suggests the pres-nce of 4 positive, outlying studies that were not balanced byegative studies. Additional investigations including referenceeview did not reveal any further peer-reviewed studies fornclusion. Although this may represent publication bias, it maylso reflect a truly significant positive relationship between PPInd SIBO. Given the controversy in the field, the clinical utilitynd impact of even a negative study makes publication bias lessikely. However, as stated earlier, the subgroup analysis of stud-es using duodenal/jejunal aspirate testing to detect SIBO re-ealed an association between PPI use and SIBO that remainedignificant even after adjusting for potential publication bias.ther expected limitations of meta-analyses, including lack of

ccess to primary data, and covariates of interest that could note accounted for individually, such as age of subjects andpecific medical diagnoses, should be considered in the assess-

ent of these findings. In addition, although they were stronglyositive, the wide CIs detected in the subgroup analyses requireare in further interpretation of the results.

Finally, caution should be taken in the translation of theseesults to clinical practice. Prior studies have shown significantverlap between symptoms associated with SIBO and manyther functional disorders of the gastrointestinal tract, such as

rritable bowel syndrome.39 – 41 However, results from SIBO test-ng have been inconsistent among patients with irritable bowelyndrome or functional gastrointestinal symptoms.42– 44 In ad-ition, variable response to antibiotic treatment for SIBO both

n terms of symptoms and follow-up testing further highlights 1

the complexity in the pathophysiology and epidemiology ofgastrointestinal symptoms, functional and motility disorders,and SIBO. Therefore, a clear causal relationship between posi-tive SIBO testing (including both duodenal/jejunal aspirateculture and breath testing) and gastrointestinal symptoms hasnot been firmly established. Because SIBO testing results, ratherthan clinical symptoms, have been the primary measured out-comes of this meta-analysis and most studies to date on therelationship between PPI and SIBO, it remains to be determinedwhether the observed increase in SIBO among PPI users actu-ally correlates with significant clinical outcomes such as symp-toms, malabsorption, or mortality.

In conclusion, this meta-analysis showed a statistically sig-nificant association between PPI use and SIBO, only when thediagnosis was made by a highly accurate testing modality (du-odenal/jejunal aspirate culture). Studies using GHBT to diag-nose SIBO did not result in a significant outcome. Prior con-flicting outcomes in the published literature may have resultedfrom inconsistencies in the diagnostic methods and cut-offvalues used in those studies. Both clinicians and patientsshould be judicious in the use of PPI and consider dose-taper-ing whenever possible. In addition, a high level of suspicionshould be raised when evaluating PPI users presenting withsymptoms or signs suggestive of SIBO. Further studies areneeded to refine the diagnostic modalities for SIBO, character-ize the underlying pathophysiology of SIBO associated withacid suppression, and assess the impact of this relationship onclinical outcomes.

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Reprint requestsAddress requests for reprints to: Walter W. Chan, MD, MPH, Division

of Gastroenterology, Brigham and Women’s Hospital, 75 FrancisStreet, Boston, Massachusetts 02115. e-mail: wwchan@partners.org;fax: (617) 525-0338.

Conflicts of interest

The authors disclose no conflicts.