doi:10.1002/jgh3.

12045

O R I GI N AL A R T IC L E

Risk of small intestinal bacterial overgrowth in patients

receiving proton pump inhibitors versus proton pump
inhibitors plus prokinetics
Pruthvi C Revaiah,* Rakesh Kochhar,† Surinder V Rana,† Neha Berry,† Munish Ashat,† Narendra Dhaka,†
Y Rami Reddy† and Saroj K Sinha†
Departments of *Medicine and †Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Key words Abstract

orocecal transit time, prokinetics, proton pump
Background and Aim: Intestinal dysmotility is considered a risk factor for small
inhibitor, small intestinal bacterial overgrowth.
intestinal bacterial overgrowth (SIBO). Prokinetics improve intestinal motility and are
Accepted for publication 31 January 2018.
often prescribed with proton pump inhibitors (PPIs) in patients with gastroesophageal
reflux disease (GERD) and/or functional dyspepsia. The present study aimed to evalu-
Correspondence ate the prevalence of SIBO and the orocecal transit time (OCTT) in patients taking
Dr. Saroj Kant Sinha, MD, DM PPI compared with those taking PPI plus prokinetics.
Professor, Dept. of Gastroenterology, Methods: The study is a single-center, cross-sectional study. Enrolled patients (with
Postgraduate Institute of Medical Education and age > 12 years) were divided into two groups: patients taking PPIs for more than
Research, Sector 12, Chandigarh, 160012, India. 3 months (Group A) and those taking PPIs with prokinetics for more than 3 months
Email: [email protected] (Group B) for various indications. Lactulose breath test (LBT) for OCTT and glucose
breath test (GBT) for SIBO were conducted for all patients.
Declaration of conflict of interest: None. Results: Of the 147 enrolled patients, SIBO was documented in 13.2% patients in
Author contribution: Dr Pruthvi CR was Group A versus 1.8% in Group B, P = 0.018. Median OCTT in Group A was
responsible for literature search, figures, study 130 (105–160) min compared with 120 (92.5–147.5) min in Group B (P = 0.010).
design, data collection, data analysis, data Median OCTT among SIBO-positive patients was 160 (140–172.5) min compared
interpretation, writing. Dr Rakesh Kochhar was with SIBO-negative patients, where it was 120 (103.75–150) min (P = 0.002). The
responsible for study design, data analysis and duration and type of PPI used were not associated with the occurrence of SIBO in our
data interpretation. Dr Surinder V Rana was study.
responsible for study design, data collection, data Conclusion: The use of prokinetics in patients on PPI may reduce the risk of SIBO
analysis, breath tests, and interpretation. Dr Neha
by enhancing intestinal motility and may reduce SIBO risk associated with long-term
Berry and Dr Munish Ashat were responsible for
PPI use.
literature search, figures, data analysis, data
interpretation and writing. Dr Narendra Dhaka and
Dr Y Rami Reddy were responsible for data
collection, data interpretation. Dr Saroj Kant Sinha
was responsible for study design, data collection,
data analysis, data interpretation and writing.
Financial support: None.

Introduction Small intestinal bacterial overgrowth (SIBO)4 is a clinical

condition where the proximal small intestine becomes colonized
Proton pump inhibitors (PPIs) are one of the most commonly used
with an abnormally large (>105/mL) number of gut microflora
prescriptions in outpatient settings. Usual indications for PPI1 ther-
apy are the presence of a gastroduodenal ulcer, erosive esophagitis, and is characterized by symptoms of weight loss, steatorrhea,
gastroesophageal reflux disease (GERD), Zollinger–Ellison syn- bloating, malabsorption, and vitamin deficiency. Besides the two
drome (ZES), or as part of the treatment regimen for Helicobacter main predisposing factors of elevated pH and dysmotility, other
pylori. PPIs act by irreversibly blocking the hydrogen/potassium risk factors for developing SIBO include diabetes, cirrhosis, pan-
adenosine triphosphatase enzyme system (the H+/K+ ATPase or, creatitis, irritable bowel syndrome, intestinal stricture, and surgi-
more commonly, the gastric proton pump) of the gastric parietal cally created blind loop.4,5 The gold standard for the diagnosis of
cells, thus significantly decreasing gastric acid secretion. Chronic SIBO is the culture of intestinal aspirates, but the glucose breath
acid suppression with long-term PPI leads to hypochlorhydria, test (GBT) may serve as a cheap, fairly sensitive, highly specific,
which alters the intraluminal environment to facilitate the growth noninvasive, and simpler surrogate.6,7
of the bacterial flora in the small intestine and contributes to the Previous studies8,9 have demonstrated abnormal small
proximal migration of colonic microflora.2,3 bowel motility in the pathogenesis of SIBO. Dysmotility

JGH Open: An open access journal of gastroenterology and hepatology 2 (2018) 47–53 47
© 2018 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and
John Wiley & Sons Australia, Ltd.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Small intestinal bacterial overgrowth PC Revaiah et al.

encourages the local proliferation of small bowel microflora and Hydrogen (H2)/methane (CH4) breath concentration in parts per
delays their distal progression. Prokinetics are a group of drugs million (ppm) was measured by the SC Microlyzer (Quintron,
that propel food and bacteria through the stagnant colon and may Milwaukee, WI, USA). The time taken for a ≥10 ppm increase in
assist with the clinical improvement of patients with SIBO. Pro- H2 and/or CH4 concentrations in two consecutive readings over
kinetics are often prescribed in conjunction with PPIs in patients the fasting value was defined as OCTT. Normal OCTT was mea-
with GERD and/or functional dyspepsia. There are, however, no sured to be in the range of 75–105 min as per the prior standardi-
data in the literature on the effect of the continuation of proki- zation in our laboratory.13
netics with PPIs on SIBO.
The present study aimed to evaluate the prevalence of
GBT for SIBO. For this test, patients were instructed not to
SIBO and the orocecal transit time (OCTT) in patients taking
consume a high-fiber diet 72 h prior to the test and to avoid anti-
PPI and compare these outcomes with patients taking both PPIs
biotics or probiotics 4 weeks prior to the test.12 End-expiratory
and prokinetics.
breath was collected in a one-way valve bag after a 12-h fast.
Each patient was given 75 g of glucose in 250 mL water, and
Methods breath samples were taken every 15 min for 2 h. An increase of
≥10 ppm over the fasting value in H2 and/or CH4 concentrations
Study and subjects. The study was designed as a single-
measured by the SC microlyzer in two consecutive readings was
center, cross-sectional study. Consecutive patients who were
considered evidence of SIBO.12
taking PPIs or PPIs with prokinetics (itopride or cinitapride or
The two groups were compared for various demographic
levosulpiride) for more than 3 months for Food and Drug Asso-
parameters like age, gender, body mass index (BMI), various
ciation (FDA)-approved indications of PPI were recruited from
gastrointestinal symptoms, duration of PPI use, duration of proki-
the outpatient clinic of the Department of Gastroenterology,
netics use, and so on. Point prevalence of SIBO was assessed in
Postgraduate Institute of Medical Education and Research
both the groups. OCTT was assessed in both the groups and
(PGIMER), Chandigarh, India. The study was approved by the
compared between the groups. The relationship between the risk
Ethics Committee of the Institute, and written informed consent
of SIBO and various parameters was assessed.
was obtained from all patients. Some of the FDA-approved
indications where PPIs can be used for more than 3 months
included healing of erosive esophagitis, treatment of GERD, Statistical analysis. The data were analyzed using SPSS
risk reduction for gastric ulcer (GU) associated with nonsteroi- software (IBM, Armonk, NY, USA). Descriptive statistics,
dal anti-inflammatory drugs (NSAIDs), short-term treatment and counts, and mean  standard deviation (or median with inter-
maintenance therapy of duodenal ulcers, and pathological quartile range if nonparametric distribution) were used to
hypersecretory conditions like ZES.10 Disorders for which pro- describe the study sample. The statistical test used for the analy-
kinetics are used include gastroparesis (both disease-related and sis of categorical data was the Chi-square test if the expected
iatrogenic), GERD, postoperative ileus, constipation, and intesti- number in all the cells was likely to be >5. If it was less than
nal pseudo-obstruction.11 5, then Fisher’s exact test was used. Numerical data were com-
Enrolled patients (with age > 12 years) were divided into pared using student t-test across the groups. Numerical data that
two groups: Group A: patients taking PPIs for more than did not follow a normal distribution were analyzed using the
3 months for various indications and Group B: patients taking Mann–Whitney U test. SIBO in individuals taking PPIs was
PPIs with prokinetics for more than 3 months for various indica- compared with those individuals taking PPIs with prokinetics. A
tions. Exclusion criteria included age < 12 years, pregnant/lactat- P-value less than 0.05 was considered to be significant.
ing women, patients with other comorbidities (type 2 diabetes
mellitus, hypothyroidism, celiac disease, chronic pancreatitis, cir-
rhosis, congestive heart failure or renal failure, small intestinal
Results
strictures), those with intake of any antibiotics in preceding A total of 147 patients taking PPIs alone (Group A) or PPI with
6 weeks, or unwillingness to participate in the study. PPIs used prokinetics (Group B) for more than 3 months were studied
in the study included pantoprazole (40 mg/day), rabeprazole (baseline characteristics as described in Table 1). Of these,
(20 mg/day), and omeprazole (20 mg/day). Levosulpiride was 91 patients were included in Group A, and 56 patients were
the only prokinetic used at the dose of 75 mg/day. Patient details included in Group B. The mean age of the patients was
were recorded on a predesigned proforma. Lactulose breath test 41.71  13.17 years, with a median duration of PPI use with or
(LBT) for OCTT and GBT for SIBO were performed for all without prokinetic of 6 months (range 4–18 months). Main indi-
patients after obtaining consent. cations for which PPI/PPI plus prokinetics were prescribed
included GERD (124 patients, 84.4%), chronic gastritis
LBT for OCTT. Patients were instructed not to take antibiotics (13 patients, 8.8%), and peptic ulcer disease (2 patients, 1.4%).
and/or probiotics for 4 weeks before the test and to avoid foods H. pylori status (as assessed by histopathology and serology) was
that are likely to generate hydrogen 72 h prior to the test.12 After negative in patients with peptic ulcer disease. All patients under-
a 12-h fast, the patients were asked to brush their teeth before went the LBT and GBT. At the time of enrollment in the study,
coming for the tests. LBT was started after thorough mouth patients were asked about any adverse effects of the drugs; how-
washing with 40 mL of 1% chlorhexidine solution. Lactulose ever, no patient reported any significant adverse effect. However,
syrup (10 grams of lactulose) was given to each patient to drink, a formal questionnaire to assess adverse effects was not used. All
and breath samples were collected every 15 min for 4 h. the results are summarized in Table 2, and the comparison of

48 JGH Open: An open access journal of gastroenterology and hepatology 2 (2018) 47–53
© 2018 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and
John Wiley & Sons Australia, Ltd.
PC Revaiah et al. Small intestinal bacterial overgrowth

Table 1 Baseline characteristics of patients on PPI alone (Group A) and PPI with prokinetics (Group B)

PPI only PPI + prokinetic

Overall Group A Group B P-value

Total of subjects (n) 147 91 56

Mean age (years) (mean  SD) 41.71  13.17 42.08  12.95 41.13  13.61 0.672
Age range (years) 13–75 13–75 16–75
Female:male 73:74 46:45 28:28 0.948
BMI (range) (kg/m2) 25.39 (21.46–28.25) 25.00 (21.35–27.68) 26.46 (22.06–26.46) 0.987
Median duration of PPI/PPI and 6 6 6
prokinetic intake (months)
Range of PPI/PPI and prokinetic 4–18 4–24 5–16.5
intake (months)
Indication for PPI/PPI and prokinetic
intake, n (%)
1. GERD 84.4 83.5 85.7
2. Chronic gastritis 8.8 11.0 5.4
3. GERD/chronic gastritis 4.8 3.3 7.1
4. Peptic ulcer disease 1.4 1.1 1.8
5. GERD/peptic ulcer disease 0.7 1.1
Symptoms, n (%)
1. Abdominal discomfort 82.3 82.4 82.1 0.966
2. Bloating 80.3 80.2 80.4 0.984
3. Flatulence 59.9 60.4 58.9 0.856
4. Abdominal distension 43.5 44.0 0.896
5. Diarrhea 22.4 24.2 42.9
6. Others Weakness (1.4); Weakness (2.2); 19.6 0.522
hoarseness of voice (1.4) hoarseness of voice (2.2)
PPIs used, n (%)
1. Rabeprazole 62.6 54.9 75.0 0.015
2. Omeprazole 19 22 14.3 0.249
3. Pantoprazole 18.4 23.1 10.7 0.060
Prokinetics used levosulpiride, n (%) 100 — 100 —

BMI, body mass index; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.

Table 2 Comparison of OCTT and point prevalence of SIBO in both to the SIBO-negative subgroup (median age 40.5 years)
groups (P = 0.046). The most common symptom in the sample after
being on either PPI or PPI with prokinetic for at least 3 months
Parameters PPI only PPI + prokinetic P-value
was abdominal discomfort (82.3%) followed by bloating
Group A (n = 91) Group B (n = 56)
(80.3%). Other symptoms were flatulence (59.9%), abdominal
Duration of 6 (5–16.5) 6 (4–24) 0.236 distension (43.5%), diarrhea (22.4%), weakness (1.4%), and
PPI (months) hoarseness of voice (1.4%). There was no statistically significant
OCTT (range) 130 (105.00–160.00) 120 (92.50–147.50) 0.010 difference in symptoms in either groups or SIBO-negative versus
(min) SIBO-positive patients.
SIBO, n (%)
Positive 12 (13.18) 1 (1.78) 0.018
Negative 79 (86.82) 55 (98.22) PPI used in the study. PPIs used in the study were rabepra-
OCTT, n (%) zole (62.6%), omeprazole (19%), and pantoprazole (18.4%).
Normal OCTT 20 (22.0) 17 (30.4) 0.256 There was no statistically significant association between a partic-
Delayed OCTT 68 (74.7) 34 (60.7) 0.173 ular PPI and SIBO prevalence. However, pantoprazole use dem-
Fast OCTT 3 (3.3) 5 (8.9) 0.260 onstrated a trend toward significant association with
OCTT, orocecal transit time; PPI, proton pump inhibitor; SIBO, small SIBO (P = 0.064). Similarly, the median duration of PPI in
intestinal bacterial overgrowth. the SIBO-positive group versus the SIBO-negative group was
8 (6–24) months versus 6 (4–18) months (P = 0.07), respectively.
SIBO-positive with SIBO-negative patients is described in
Table 3. GBT for SIBO. Evidence of SIBO was present in 13 (8.8%)
patients, while it was normal in 134 (91.2%) patients. The preva-
Age and symptoms. SIBO-positive patients were found lence of SIBO was greater in Group A (13.18%) than Group B
to be statistically younger (median age 36 years) as compared (1.78%) (P = 0.018). With regard to GBT, 23.1% (n = 3)

JGH Open: An open access journal of gastroenterology and hepatology 2 (2018) 47–53 49
© 2018 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and
John Wiley & Sons Australia, Ltd.
Small intestinal bacterial overgrowth PC Revaiah et al.

Table 3 Comparison of SIBO-positive versus SIBO-negative group among SIBO-positive patients was 160 (140–172.5) min compared
to SIBO-negative patients where it was 120 (103.75–150) min
Parameters SIBO SIBO P-value
(P = 0.002).
positive negative
The symbiotic relation between a human and his or her
(n = 13) (n = 134)
gut microbiome has flourished over millions of years.14
Total, n (%) 13 (8.8) 134 (91.2) 0.018 Human genetics, geography, diet, exposure to antibiotics, and
Age, n (range) 36 (25–43.5) 40.5 (33–50.25) 0.046 chronic gastrointestinal inflammatory states are some of the
(years) major modifiers of gut flora.15–18 The two processes that most
Diarrhea, n (%) 4 (30.8) 29 (21.6) 0.489 commonly predispose people to bacterial overgrowth are
Abdominal 12 (92.3) 109 (81.3) 0.466 diminished gastric acid secretion and small intestine dysmoti-
discomfort, n (%) lity.5,19,20 SIBO is defined as a bacterial population in the
Flatulence, n (%) 11 (84.6) 77 (57.5) 0.057 small intestine exceeding 105–106 organisms/mL. The use of
Abdominal 12 (92.3) 106 (79.1) 0.465 PPIs has demonstrated a predisposition to SIBO by altering
bloating, n (%)
the intraluminal environment and bacterial flora.5,21 Many of
Abdominal 8 (61.5) 56 (41.8) 0.170
the studies regarding the prevalence and incidence of SIBO in
distension, n (%)
patients taking PPI have been performed in the Western popu-
Gender, n (%)
lation, while the data on the southeast populations are limited.
Male 8 (61.5) 66 (49.3) 0.398
Female 5 (38.5) 68 (50.7)
Apart from geographical differences, the Indian population has
BMI (kg/m2) 25.33  5.49 25.35  4.65 0.987 different dietary preferences and is exposed to different envi-
Type of PPI, n (%) ronment. Therefore, this population’s gut microbiome is differ-
Rabeprazole 8 (61.5) 84 (62.7) 1.000 ent compared to Western populations.22 Hence, the prevalence
Omeprazole 0 (0.0) 28 (20.9) 0.130 and severity of SIBO in Indian population may vary. Of
Pantoprazole 5 (38.5) 22 (16.4) 0.064 91 patients taking PPI who underwent GBT in our study,
Duration of PPI 8 (6–24) 6 (4–18) 0.071 12 patients (13.18%) had SIBO. The percentage of patients
(range) (months) positive for SIBO in patients taking PPI was lower compared
OCTT, n (range) 160 (140–172.50) 120 (103.75–150.00) 0.002 to previous studies. In earlier studies, Compare et al. reported
(min) this value to be 11 of 42 (26.19%), Lombardo et al. reported
OCTT, n (%) it to be 100 of 200 (50%), and Ratuapli et al. reported it to be
Normal OCTT 0 (0.0) 37 (27.6) 0.039 126 of 566 (22%) (Table 4).9,23–30
Delayed OCTT 13 (100) 89 (70.6) 0.023 We have used GBT for the diagnosis of SIBO instead of
Fast OCTT 0 (0.0) 8 (6) 1.000 LBT as various studies12,31 have demonstrated GBT to have
BMI, body mass index; OCTT, orocecal transit time; PPI, proton pump greater diagnostic accuracy than LBT. In another study from our
inhibitor; SIBO, small intestinal bacterial overgrowth. center,12 LBT and GBT were compared to diagnose SIBO among
175 diarrhea- predominant IBS patients and 150 healthy controls.
The study concluded that positive GBT for SIBO was signifi-
patients had a methane peak, and 76.9% (n = 10) patients had a
cantly higher in patients than controls; however, when using LBT,
hydrogen peak.
a positive test was not significantly different in patients and con-
trols. The advantage of GBT is that glucose is readily absorbed in
LBT for OCTT. OCTT was delayed in 102 (69.4%) and was
the small bowel and cannot reach the colon, thereby avoiding
normal in 45 (30.6%) patients. It was delayed in 68 (74.7%)
false positive results. We have used a cut-off increase of ≥10 ppm
patients in the PPI only group versus 34 (60.7%) patients in the
in H2 and/or CH4 concentrations from baseline to indicate a posi-
PPI + prokinetic group. Median OCTT was more prolonged in
tive breath test. The most frequently used cut-off value for test
Group A (130 min) compared with Group B (120 min)
positivity is 10–12 ppm.32 In the previous studies12,13 from our
(P = 0.010). OCTT was more prolonged in SIBO-positive patients
center as well in recent reviews,33,34 a cut-off value of 10 ppm
compared to SIBO-negative patients (160 min vs 120 min,
from baseline has been used to indicate a positive breath test.
P = 0.002). None of the SIBO-positive patients had normal OCTT
The prevalence of SIBO was low in our study. The preva-
(P = 0.039). OCTT was significantly prolonged among the
lence of parasitic infection and gut colonization is higher in
12 SIBO-positive patients in PPI group compared to SIBO-
Indian and southeast Asian populations as compared to the
negative patients in the PPI group (160 vs 120 [105–150] min,
West.35 This leads to broader diversity and superior stability of
P = 0.006).
gut microbiota, which may explain the decreased prevalence of
SIBO in this subgroup.36 Secondly, the southeast Asian patient
Discussion group is more prone to developing acute diarrhea, which further
In our single-center, cross-sectional study on 147 patients, SIBO decreases the concentration of gut microbiota.37 There is also a
was documented more frequently (12/91, 13.2%) in Group A higher prevalence of SIBO with increasing age as adults have a
(PPI only) than in Group B (1/56, 1.8%, PPI + prokinetics) higher likelihood of gastrointestinal surgery and/or medication
(P = 0.018). Median OCTT in Group A was 130 (105–160) min use, which may alter the intraluminal environment.38 In addition,
compared to Group B, in which it was 120 (92.5–147.5) min factors that increase the risk of SIBO (e.g. altered gut motility,
(P = 0.010). OCTT was prolonged in 68 of 91 patients (74.7%) in diverticulosis, and atrophic gastritis) are more prevalent in adults.
Group A and 34 of 56 (60.7%) patients in Group B. Median OCTT The average age of our patients was 36 years in Group A and

50 JGH Open: An open access journal of gastroenterology and hepatology 2 (2018) 47–53
© 2018 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and
John Wiley & Sons Australia, Ltd.
PC Revaiah et al. Small intestinal bacterial overgrowth

Table 4 Existing literature demonstrating the association of PPI and SIBO

Study and year Test type Geography PPI Cut-off Sample size SIBO positives Mean age PPI used Duration of PPI
association value of PPI group in PPI group (%) of whole
with SIBO (ppm) sample
(years)

Fried et al. Aspirates Switzerland Yes NA 25 56 53.4 Omeprazole 5.7 weeks of

(1994)24 mean duration
Thorens et al. Aspirates Switzerland Yes NA 19 53 42 Omeprazole 4 weeks
(1996)28
Hutchinson GHBT United Kingdom No H2 > 20 22 45 78.5 Omeprazole Median duration
et al. (1997)29 of 9.5 months.
Pereira et al. Aspirates United Kingdom Yes NA 8 62.5 76 Omeprazole 8 weeks
(1998)26
Lombardo GHBT Italy Yes H2 > 10 200 50 37 Esomeprazole Median duration
et al. (2010)25 Lansoprazole of 36 months
Omeprazole
Rabeprazole
Pantoprazole
Compare et al. GHBT Italy Yes H2 > 12 42 26.19 37 Esomeprazole 6 months
(2011)23
Choung et al. Aspirates United States No NA 249 10 53 NA NA
(2011)30
Ratuapli et al. GHBT United States No H2 > 20 566 22 60.9 NA NA
(2012)27 or CH4 > 15
Jacobs et al. Aspirates United States Yes NA 65 58.4 44 NA NA
(2013)9 (103 CFU/mL)
32.2
(105 CFU/mL)

CFU, colony-forming unit; GHBT, glucose hydrogen breath test; H2, hydrogen; CH4, methane; NA, not available; ppm, parts per million; PPI, proton
pump inhibitor; SIBO, small intestinal bacterial overgrowth.

40.5 years in Group B. Hence, younger age may influence the SIBO-positive patients compared to SIBO-negative patients
low number of SIBO-positive results. (160 [140–172.5] min vs 120 [103.7–150] min, P = 0.002). This
The most common symptom in SIBO-positive patients in finding also supports the hypothesis that SIBO is related to
our study was abdominal discomfort and bloating. This was simi- slower gastrointestinal transit.
lar to other previous studies where Sachdev et al.19 and Lom- Prokinetic medications11 enhance the contractility of the
bardo et al.25 also showed bloating to be the most common GI tract, correct gastric dysrhythmias, and promote the move-
symptom. In our study, the point prevalence of SIBO did not dif- ment of luminal contents in the anterograde direction. Prokinetic
fer significantly among the used PPI, namely, pantoprazole, rabe- agents have been shown to improve intestinal motility, and use
prazole, and omeprazole. However, pantoprazole demonstrated a of this therapeutic approach has been proven to be useful in the
trend for significant association with SIBO (P = 0.06). In previ- reduction of bacterial overgrowth. Prokinetics such as cisapride,
ous studies, omeprazole was associated with increased incidence erythromycin, metoclopromide, domperidone, levosulpiride, ito-
of SIBO in contrast to our study.24,26,28,39 Whether a particular pride, and cintapride accelerate gastric emptying and improve
PPI increases the risk of SIBO or not needs to be explored. gastrointestinal symptoms in patients with functional dyspepsia.
Small intestinal transit time is delayed in SIBO. Roland In our study, all the patients in Group B (n = 56) were using
et al.40 demonstrated that patients with underlying SIBO have levosulpiride as a prokinetic. Mulyadi et al.45 from Indonesia
significant delays in small intestinal transit time compared with showed that SIBO occurred in 61.8% patients on placebo com-
those without (6.6 h vs 4 h). Ghoshal et al.7 demonstrated that pared to 2.9% on domperidone. Similarly, in the present study,
OCTT was longer in patients with SIBO than in those patients SIBO occurred in fewer patients (1.8%) taking levosulpiride with
without SIBO (170 [60–250] min vs 120 [50–290 min], PPI compared to patients taking PPIs alone (13.2%), P = 0.018.
P = 0.02). Cumulative evidence suggests that OCTT is delayed We did not come across any other study documenting the inci-
in patients with SIBO and comorbid inflammatory bowel dis- dence of SIBO in patients on prokinetics with PPI compared to
ease, gall stone diseases, diabetes and cirrhosis with minimal PPI alone and whether the addition of prokinetic to a PPI reduces
hepatic encephalopathy compared to the SIBO-negative sub- the incidence of SIBO.
group in these studies.41–44 In our study, median OCTT was Long-term PPI intake is associated with SIBO. The
more prolonged in the PPI group compared to PPI + prokinetics median duration of drug intake in our study was 6 (4–24) months
group (130 [105–160] min vs 120 [92.5–147.5] min, in Group A and 6 (5–16.5) months in Group B. Median duration
P = 0.010). Median OCTT was also significantly prolonged in of PPI in the SIBO-positive group versus the SIBO-negative

JGH Open: An open access journal of gastroenterology and hepatology 2 (2018) 47–53 51
© 2018 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and
John Wiley & Sons Australia, Ltd.
Small intestinal bacterial overgrowth PC Revaiah et al.

group was 8 months versus 6 months (P = 0.07), respectively. occurrence of SIBO in our study. Hence, the addition of proki-
Although not statistically significant, these outcomes demonstrate netics to the treatment of patients on PPI may reduce the risk of
that patients with a longer duration of PPI are more prone to SIBO associated with the prolonged use of PPI; however, it
develop SIBO. Compare et al.23 demonstrated that the incidence would be prudent to look for the side effects of prokinetics in
of SIBO increases when the duration of PPI intake is longer than patients who receive these for a prolonged period.
6 months, which is in concordance with our study. Lombardo
et al.25 demonstrated that the incidence of SIBO increases when
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JGH Open: An open access journal of gastroenterology and hepatology 2 (2018) 47–53 53
© 2018 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and
John Wiley & Sons Australia, Ltd.