Effect of vitamin D on gastrointestinal symptoms and ... · Effect of vitamin D on gastrointestinal symptoms and health-related quality of life in irritable bowel syndrome patients:

Effect of vitamin D on gastrointestinal symptoms and

health-related quality of life in irritable bowel syndrome

patients: a randomized double-blind clinical trial

A. ABBASNEZHAD,* R. AMANI,† E. HAJIANI,‡ P. ALAVINEJAD,‡ B. CHERAGHIAN§ & A. GHADIRI¶

*Nutrition and Metabolic Diseases Researcher Center, Department of Nutrition, Ahvaz Jundishapur University of Medical

Sciences, Ahvaz, Iran

†Diabetes Research Center, Health Research Institute, Department of Nutrition, Ahvaz Jundishapur University of Medical

Sciences, Ahvaz, Iran

‡Research Center for Infectious Diseases of the Digestive System, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

§Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

¶Research Center for Infectious Diseases of Digestive System, Department of Biostatistics and Epidemiology, School of Public

Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Key Points

• There is evidence supporting the role of inflammation in the pathogenesis of irritable bowel syndrome (IBS).

Furthermore, psychological factors play an important role in the onset and progress of IBS.

• Vitamin D was effective in alleviating GI symptoms in IBS patients (except for the patients’ dissatisfaction with

bowel habits). Moreover, the IBS severity score and QoL significantly improved following vitamin D

supplementation.

• This study implies that vitamin D3 may have beneficial effects in IBS.

Abstract

Background Low-grade mucosal inflammation and

immune activation are involved in the pathogenesis of

irritable bowel syndrome (IBS). Furthermore, IBS

symptoms are associated with a significantly higher

prevalence of psychological distress, which in itself

results into an impaired quality of life (QoL). Vitamin

D could ameliorate the symptoms of patients suffering

from IBS through its beneficial effects on psycholog-

ical factors and inflammation. Methods A total of 90

IBS patients participated in this double-blind, random-

ized, placebo-controlled study. Participants were

randomly selected to receive either 50 000 IU vitamin

D3 or a placebo fortnightly for a period of 6 months.

Patients reported their IBS symptoms at the baseline and

monthly during intervention periods. The IBS severity

scoresystem(IBSSS)andIBS-specificQoLquestionnaires

were used at the baseline and postintervention. Key

ResultsOver the 6-month intervention period, a signif-

icantly greater improvement in IBS symptoms such as

abdominal pain and distention, flatulence, rumbling,

and overall gastrointestinal (GI) symptoms (except

dissatisfaction with bowel habits) was observed in the

patients receiving vitamin D as compared to the

placebo group. The IBSSS and the IBS-QoL scores in

the vitamin D group significantly improved compared

to the placebo group postintervention (mean IBSSS

score change: �53.82 � 23.3 vs �16.85 � 25.01,

p < 0.001, respectively; mean IBS-QoL score change:

14.26 � 3 vs 11 � 2.34, p < 0.001, respectively). Con-

clusions & Inferences Vitamin D seems to be an

effective and safe option to improveQoLand symptoms

of IBS. ClinicalTrials.gov (NCT02579902).

Address for CorrespondenceReza Amani, PhD, R Nutr., Health Research Institute,Diabetes Research Center Department of Nutrition, AhvazJundishapur University of Medical Sciences, Golestan Blvd,Ahvaz; PO Box: 61357-15794, Iran.Tel: +98 916 313 9856; fax: +98 613 3738 330;e-mail: [email protected]: 29 January 2016Accepted for publication: 11 April 2016

© 2016 John Wiley & Sons Ltd 1533

Neurogastroenterol Motil (2016) 28, 1533–1544 doi: 10.1111/nmo.12851

Neurogastroenterology & Motility

Keywords gastrointestinal symptoms, health-related

quality of life, IBS severity score, irritable bowel

syndrome, vitamin D.

Abbreviations: GI, gastrointestinal; IBD, inflammatory

bowel disease; IBSSS, IBS severity score system; QoL,

quality of life; VDD, vitamin D deficiency.

INTRODUCTION

Irritable bowel syndrome (IBS) is a chronic condition

characterized by abdominal discomfort or pain, altered

bowel habits, abdominal distension, and flatulence

with symptoms ranging from mild to severe.1 Abnor-

malities of the brain–gut axis function and immune

system, visceral hypersensitivity, and disturbances of

gastrointestinal (GI) motility have been associated

with IBS.2–4 Moreover, IBS symptoms are associated

with a significantly higher prevalence of psychological

distress which results in impaired social and personal

functions and a sense of well-being and a decline in the

patient’s quality of life (QoL).4 Approximately one

third of the IBS patients fail to respond to existing

treatments,5,6 and 16–33% of outpatients seek alterna-

tive medicine consultation for their symptoms.6–9

Vitamin D has long been recognized as a major

regulator of calcium and phosphorus metabolism.10

Several recent studies have yielded new insights into

the role of vitamin D such as its immunomodulatory

and anti-inflammatory actions.11 The rate of vitamin D

deficiency (VDD) has been estimated to be 30–50%worldwide,10 which is also a common percentage in GI

disease.12 It is of note that recent research has

indicated an increased risk of osteoporosis and related

fractures in IBS patients; in addition to the fact that

VDD has also been reported in these patients.13,14 A

case study on an IBS patient taking a high-dose

(3000 IU daily) vitamin D reported that the IBS symp-

toms were improved following supplementation, and

recurred after supplement cessation.14 Furthermore,

analysis of social media (blogs/forums) indicated that

of 37 IBS patients, whom reported themselves as being

vitamin D deficient, 70% described improvements in

their symptoms when using high-dose vitamin D

supplementation.14 However, such a deficiency and

the temporal association of the potential relationship

between vitamin D and IBS remain to be determined.

Thus, vitamin D supplementation could be consid-

ered to have beneficial effects through the modulation

of immune response and inflammation, which in turn,

could affect the altered gut function as the basis for the

generation of IBS symptoms.15 Furthermore, the

homeostasis of the intestinal mucosal barrier is

affected by 25(OH)D3, and mucosal damage commonly

occurs in VDD.16 It has also been observed that VDD is

common in patients with anxiety, depression, and

fibromyalgia,17 appearing with greater frequency in IBS

patients.18 It is believed that vitamin D supplementa-

tion can improve these symptoms.19

Vitamin D supplementation could have a beneficial

effect on patients with IBS; accordingly, to explore the

effects of vitamin D supplementation on symptoms,

severity score, and QoL in IBS patients, the following

trial has been conducted. To our best knowledge, this

study is the first work published in this area.

MATERIALS AND METHODS

Participants

Participants included 90 men and women between the ages of 18and 70 years. According to the Rome III Diagnostic Criteria forFunctional GI Disorders for the diagnosis of IBS,20 patients wererecruited from the outpatient clinic at the Jundishapur Universityof Medical Sciences, Ahvaz, Iran, by an attendant gastroenterol-ogist after medical examination in February and March 2015.

Participants were asked to take part at the regularly follow-upvisits, provide adequate tracking information, and complete thequestionnaires and the treatmentprocedureuntil the endof thestudy.

The exclusion criteria were any evidence of abdominal surgeryor radiation, celiac disease, or other primary GI illnesses, GIinfection obscuring IBS symptoms, using total parenteral nutri-tion therapy in the last 6 months, pregnancy, lactation, andalcohol consumption. In addition, concurrent chronic diseasessuch as diabetes, renal failure, and kidney stones, diagnosed and/or treated malignancy in the past 5 years, serum calcium levelsgreater than 10.6 mg/dL, and intake of vitamin D, omega-3,vitamin E, and calcium supplements or being on a special diet ormedication regimen during the last 6 months were considered asadditional exclusion criteria.

A gastroenterologist assessed the patients to ensure that allcriteria were met. Patients with IBS were subclassified further asdiarrhea predominant (IBS-D), constipation predominant (IBS-C),and those with alternating bowel habit (IBS-A).

Study design

The study was a 6-month randomized, double-blind, placebo-controlled trial with parallel design. The sample size was calcu-lated 37 subjects in each group, based on changes in the IBSseverity score postintervention with a difference of 50 mmbetween the effect of vitamin D and placebo, a standard deviation(SD) of 70.8 for the intervention group, and an SD of 78.5 for theplacebo group, obtained from a similar work,21 with a power of80%, at a 0.05 level of statistical significance. Considering thelength of treatment, 45 subjects were finally enrolled in eachgroup (1 : 1 ratio) according to a computer-generated blockedrandomization list with a block size of 6. Participants visited thegastroenterologist during three separate periods: at the baseline,during the third month, and at the end of the study. A researcher,who did not have any clinical participation in the study, placedthe supplements and placebos into numbered bottles based on a

© 2016 John Wiley & Sons Ltd1534

A. Abbasnezhad et al. Neurogastroenterology and Motility

random list. Another colleague, who was not aware of the randomsequences and who was not involved in the trial, assigned thenumbered bottles to the patients.

After allocation during the baseline visit, the participants wereasked to fill in all the questionnaires. In addition, they were askedto go to the lab for further laboratory blood sampling in the nextday and then, they were allowed to start having treatment pearls.All subjects visited the gastroenterologist at the end of the study,and were asked to fill in the questionnaires again. Secondary bloodsampling was done at the end of the trial. Every month, all theparticipants were contacted to remind them about the symptomquestionnaire, taking the treatment pearls and to report if therewere any side effects. Patient compliance was followed byreturning unused pearls to the researchers. Anthropometricmeasures such as height, weight, waist and hip circumference,and also body fat percentage were measured pre- and postinter-vention. Disease history, demographic data, history of diet, usingmedications and supplements, physical activity level assessed bythe short form of the International Physical Activity Question-naire,22 and a complete physical examination of each subject werealso assessed. All the participants, researchers, and the physicianwere blind to the allocations using the random codes until thestatistical analysis was completed. The study protocol wasapproved by the Medical Ethics Committee at the AhvazJundishapur University of Medical Sciences (Registration No.ir.ajums.rec.1394.306). All subjects signed the written informedconsent to participate in the study. The trial was registered atclinicaltrials.gov (NCT02579902).

Endpoints

The primary outcome was the measurement of IBS severity scoreat the baseline and postintervention. Secondary outcomes werethe measurement of GI symptoms (abdominal pain, abdominaldistention, flatulence, rumbling, dissatisfaction with bowelhabits, and overall GI symptom) monthly and also IBS-QoL pre-and postintervention.

Intervention

During the intervention, all patients received either one oral pearlconsisting of 50 000 IU vitamin D3 (D-Vitin 50 000; ZahraviPharm Co, Tabriz, Iran) or a placebo (Zahravi Pharm Co)fortnightly. Placebo pearls contained edible paraffin similar incolor, shape, size, and package to the vitamin D3 ones.

Gastrointestinal symptoms and severity scoring

For assessing the IBS severity, the IBS severity score system(IBSSS)23 was used at the baseline and at the end of the study asmentioned above. Irritable bowel syndrome severity score systemis validated for use in IBS patients, which included five clinicallyrelevant items during a 10-day period: (i) severity of abdominalpain, (ii) frequency of abdominal pain, (iii) severity of abdominaldistention or tightness, (iv) dissatisfaction with bowel habits, and(v) interference of IBS with life in general.23 Each item was scoredon a scale from 0 to 100, and the sum of these five items was thescore of IBS severity (range 0–500). Scores of 75–175, 175–300, and>300 indicated mild, moderate, and severe cases, respectively. Areduction in the score of 50 or over was regarded as a clinicallysignificant improvement.23 Moreover, abdominal pain and dis-tension, flatulence, rumbling, dissatisfaction with bowel habits,and overall GI symptoms were evaluated at the baseline and

monthly during the intervention using a self-reporting 100-mmvisual analog scale, where 0 indicated no symptoms and 100represented the worst symptoms ever experienced. Gastrointesti-nal symptoms questionnaires were given to the patients, and theywere asked to fill it in at home every month during the treatment.At the end of the trial, the questionnaires were elicited by theresearchers.

Quality of life

TheQoLwasassessedat thebaseline andat theendof the studyusinga self-reportQoLmeasure specific to IBS (IBS-QoL)with 34 items and8 subscales including dysphoria, interference with activity, bodyimage, health worry, food avoidance, social reaction, sexual, andrelationships.24 The individual responses to the 34 itemswere summed and averaged for a total score and then transformedto a 0–100 scale. The higher scores indicated a better QoL.24

Collection of blood samples

Blood samples were collected at the baseline and the end of thestudy. Each time, 5 mL of blood sample was drawn. Serums ofsamples were frozen at �20 °C immediately and then stored at�80 °C until further laboratory analyses were done.

Laboratory analyses

Vitamin D status was quantitatively assessed by measuring serum25(OH)D3 levels using radioimmunoassay (ImmunodiagnosticSystems, Boldon, UK), and serum calcium was measured using aphotometric test (Arsenaco III Method; Pars Azmoon Co, Tehran,Iran) in the Central Laboratory at the Ahvaz Jundishapur Univer-sity of Medical Sciences. The Vitamin D status was categorizedbased on serum concentrations of 25(OH)D3 as sufficient (≥30 ng/mL), insufficient (≥20 to <30 ng/mL), and deficient (<20 ng/mL).10

During each laboratory analyses, technicians were blind to thecase–control status.

Statistical analysis

All analyses were done on the intention-to-treat populationcorresponding to the subjects having consumed at least 1 doseof treatment. IBS symptoms were analyzed using an ANOVA modelwith repeated measurements in which the baseline measurementof an outcome, treatment, time, and interaction between time andtreatment were treated as fixed effects, and the subject was treatedas a random effect. Irritable bowel syndrome severity score systemand IBS-QoL were analyzed by paired t-test or Wilcoxon pairedrank test for within-group comparisons (pre-and postinterventionvalues in each group). Comparisons of changes (endpoint minusbaseline) after 6 months of intervention between the groups weredone by independent t-test or Mann–Whitney U-test. Data werereported as mean � SD or median (25th, 75th percentile) forparametric and non-parametric data, respectively. Student’s t-test,chi-squared test, or Fisher’s exact test were used for baselinecharacteristic data for between the groups comparisons, whenappropriate. Distribution of data related to normality was assessedusing a Kolmogorov–Smirnov test.

All statistical analyses were carried out using SPSS version 16statistical software (SPSS Inc, Chicago, IL, USA). The mostimportant outcomes were presented at 95% confidence intervals(CI). For all tests, two-sided p-values <0.05 were considered


Volume 28, Number 10, October 2016 Effect of vitamin D in IBS patients

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statistically significant. However, in the comparison between thegroups on IBS symptom scores in any time point, two-sided p-values <0.007 were considered as being statistically significant.

RESULTS

Of 114 potentially eligible patients, 90 subjects were

enrolled and 45 were randomly allocated to vitamin D

or placebo groups. Among the enrolled patients, 5

discontinued the study (1 subject in the vitamin D

group was unreachable because of displacement, and in

the placebo group 3 were unreachable because of

displacement and 1 due to unwillingness). The flow-

chart describes the patients’ allocation throughout the

study (Fig. 1).

Baseline characteristics

The mean age of the subjects was 37.9 (range 18–73 years) and more than two thirds of the patients were

female. Irritable bowel syndrome classification of the

subjects at baseline demonstrated that constipation,

diarrhea, and alternating bowel habit subclasses were

34.1%, 25.9%, and 40%, respectively. In addition,

15.3%, 61.2%, and 23.5% of the patients had mild,

moderate, and severe disease severity, and the mean

IBSSS score for all patients was 248.5. Most patients

had experienced symptoms of IBS for more than 5 years

(75.3%). Compliance rate was 93.2% vs 92.7% in the

vitamin D and placebo groups, respectively. There

were no significant differences in terms of demo-

graphic, clinical characteristics, anthropometric, diet-

ary variables (data not shown), physical activity, type

of IBS, and IBS-QoL score between the two groups as

indicated in Table 1. In addition, there were no differ-

ences between the treatment and placebo groups

regarding the serum 25(OH)D3 and calcium concentra-

tions at the baseline. History of disease and the use of

medication were both comparable between the trial

Figure 1 Flowchart of the patients through

the study.



groups. During the study, there were no serious adverse

events such as hypercalcemia. A few minor headaches

and back pains were reported in both groups.

Serum vitamin D and calcium concentrations

As expected, serum 25(OH)D3 levels significantly

increased from baseline following a 6-month vitamin

D supplementation (p < 0.001, Table 2); however, it

never exceeded the normal levels in the vitamin D

group. Furthermore, the mean change in serum 25(OH)

D3 levels in the vitamin D group was significantly

greater than the placebo group (p < 0.001, Table 2). At

the baseline, the percentage of patients who had serum

25(OH)D3 concentrations <20, 20–30 ng/mL, and over

30 ng/ml was 65.9%, 18.2%, and 15.9%, in vitamin D

group. These values changed to 0, 2.3%, and 97.7%,

respectively, at the end of the study. In the placebo

group, the corresponding values were 63.4%, 22%, and

14.6% at baseline vs 63.4%, 17.1%, and 19.5%,

respectively, after 6 months. There were no significant

differences between the baseline and postintervention

periods in terms of serum calcium concentrations in

vitamin D and placebo groups or was there a significant

difference among the mean serum calcium

changes between both groups at the end of the study

(Table 2).

IBS symptoms

Irritable bowel syndrome severity score system score

was significantly improved from the baseline in both

wings (Table 3). The mean change in the IBSSS score in

the vitamin D group was significantly greater in the

postintervention phase than in the placebo group

(�53.82 � 23.3 vs �16.85 � 25.01, p < 0.001, respec-

tively). The overall placebo effect for the severity score

in this study was 27%.

All the IBS symptoms significantly improved after

6 months in both groups (Table 4). As Fig. 2 indicates,

in the vitamin D group, all symptoms except dissatis-

faction with bowel habits showed a significantly

higher improvement (p < 0.05) than those of the

placebo group.

Abdominal pain, flatulence, abdominal distention,

and rumbling were significantly improved from the

first month when compared to the baseline in both

groups (p < 0.05, Fig. 2). Dissatisfaction with bowel

habits did not indicate any significant improvement in

either the vitamin D or control group until the second

month when compared with the baseline (mean

score � SD: 33.55 � 5.94 vs 38.75 � 9.73; p < 0.05

and 34.51 � 7 vs 36.90 � 6.34; p < 0.05, respectively).

The overall GI symptoms improved significantly

from the first month as compared to the baseline in the

vitamin D group (mean score � SD: 40.52 � 9.51 vs

45.07 � 9.03; p < 0.05). However, in the placebo group

it did not decrease significantly until the second month

(mean score � SD: 42.24 � 9.51 vs 45 � 8.50;

p < 0.05). Comparing the effect of vitamin D vs placebo

on symptoms score showed significantly higher

improvements in the scores of abdominal pain and

distention, flatulence, and overall GI symptoms in

months 4, 5, and 6 in vitamin D group (p < 0.007,

Fig. 2). As Fig. 2E shows, vitamin D improved the

rumbling score more (p < 0.007) in months 5 and 6.

However, the symptom score of dissatisfaction with

Table 1 Baseline demographic and clinical characteristics in 85

patients with IBS

Characteristics

Vitamin D

(n = 44)

Placebo

(n = 41) p-value

Age, years 37.45 � 8.11 38.34 � 9.85 0.65

Female* 28 (63.6) 29 (70.7) 0.49

IBS subtypes*

IBS-C 15 (34.1) 14 (34.1) 0.68

IBS-D 13 (29.5) 9 (22)

IBS-A 16 (36.4) 18 (43.9)

IBS severity*

Mild 6 (13.6) 7 (17.1) 0.87

Moderate 28 (63.6) 24 (58.5)

Severe 10 (22.7) 10 (24.4)

Symptoms

Overall 45.07 � 9.03 45 � 8.50 0.96

Abdominal pain 46.36 � 7.03 44.8 � 6.51 0.30

Abdominal

distention

43.05 � 8.33 41.9 � 9.72 0.56

Flatulence 40.75 � 6.72 42.15 � 8.64 0.40

Rumbling 39.91 � 7.56 36.83 � 7.08 0.06

Dissatisfaction

with

bowel habits

38.75 � 9.73 36.9 � 6.34 0.30

IBS-QoL 60.51 � 9.50 59.05 � 11.55 0.52

IBSSS 250.5 � 59.71 246.34 � 59.70 0.75

Duration of IBS symptoms*

1–5 years 12 (27.3) 9 (22) 0.57

>5 years 32 (72.7) 32 (78)

Family history of IBS*

Yes 14 (31.8) 15 (36.6) 0.64

No 30 (68.2) 26 (63.4)

BMI, kg/m2 25.21 � 2.72 24.98 � 2.90 0.71

Body fat percentage 27.6 � 6.08 28.24 � 6.37 0.64

Serum 25(OH)D3,

ng/mL

19.65 � 10.35 18.62 � 11.23 0.66

Serum Calcium,

mg/dL

9.03 � 0.30 8.96 � 0.32 0.31

Physical activity,

MET-min/week

356.95 � 273.53 324.42 � 217.68 0.55

*Data are numbers (%), and were analyzed by chi-squared test or

Fisher’s exact test. All data are shown as mean � SD, and analyzed by

two-sample t-test unless otherwise indicated. IBS, irritable bowel

syndrome; BMI, body mass index; MET, metabolic equivalent of task;

IBS-C, constipation subtype; IBS-D, diarrhea subtype; IBS-A, alternat-

ing subtype; IBS-QOL, Irritable bowel syndrome quality of life; IBSSS,

IBS severity score system.



bowel habits did not show any significant differences

between the groups until the month 6 (p < 0.007,

Fig. 2D).

Moreover, there were no significant differences in

the mean change in GI symptoms score and the IBSSS

between 25OHD3 deficient (insufficient and deficient

cases) and replete individuals (Fig. 3); however,

changes in vitamin D deficient subjects were higher.

There were no significant group-by-time interactions

in any of the symptoms measured.

Quality of life

At the end of the study, the overall score of IBS-QoL

significantly improved in both groups; however, greater

improvement was seen in the vitamin D group

(p < 0.001, Table 5). In addition, all subscale scores of

Variables

Vitamin D (n = 44) Placebo (n = 41)

p-value*Value p-value† Value p-value†

Serum 25(OH)D3, ng/mL

Baseline 19.65 � 10.35 18.62 � 11.23

6 months 52.78 � 12.42 20.91 � 10.93

Change‡ 33.12 � 9.65 <0.001 2.28 � 7.76 0.07 <0.001Serum calcium, mg/dL

Baseline 9.03 � 0.30 8.96 � 0.32

6 months 9 � 0.25 8.95 � 0.27

Change �0.03 � 0.10 0.06 �0.01 � 0.12 0.53 0.53

*p-value for comparing the changes of variables between the groups. Two-sample t-test was

used. †p-value for comparing baseline, with endpoint values within each group. Paired sample t-

test was used. ‡End–baseline. Values are expressed as mean � SD for parametric data and median

(25th, 75th percentiles) for non-parametric data.

Table 2 Within- and between-group com-

parisons of the changes from baseline to

endpoint measures for 25(OH)D3 and cal-

cium in vitamin D and placebo groups of IBS

patients

IBSSS



Baseline 250.5 � 59.71 246.34 � 59.70

6 months 196.66 � 69.30 229.50 � 73.13

Change‡ �53.82 � 23.30 <0.001 �16.85 � 25.01 <0.001 <0.001

*p-value for comparing the changes in variables between the groups. Two-sample t-test was used.†p-value for comparing baseline with endpoint values within each group. Paired sample t-test was

used. ‡End–baseline. Values are expressed as mean � SD. IBSSS, IBS severity score system.



endpoint measure for IBSSS in vitamin D

and placebo groups of IBS patients

Table 4 Irritable bowel syndrome symptoms: overall GI symptoms, abdominal pain, bloating, rumbling, abdominal distention, and dissatisfaction

with bowel habits at the baseline and the end of the study period

Symptoms


Baseline After 6 months p-value* Baseline After 6 months p-value*

Abdominal pain 46.36 � 7.03 29.54 � 12.20 <0.001 44.80 � 6.51 38.30 � 12.92 0.001

Change† �16.81 � 11.03 �6.51 � 11.71

Abdominal distention 43.05 � 8.33 27.57 � 10.50 <0.001 41.90 � 9.72 35.39 � 12.82 0.001

Change �15.48 � 8.67 �6.51 � 10.73

Dissatisfaction with bowel habits 38.75 � 9.73 27.16 � 4.56 <0.001 36.90 � 6.34 33.05 � 11.83 0.011

Change �11.59 � 10.20 �3.85 � 11.97

Flatulence 40.75 � 6.72 26.65 � 5.88 <0.001 42.15 � 8.64 36 � 10.08 <0.001Change �14.1 � 7.8 �6.15 � 11.85

Rumbling 39.91 � 7.56 25.86 � 5.55 <0.001 36.83 � 7.08 32.95 � 11.67 0.009

Change �14.045 � 7.53 �3.9 � 11.81

Overall 45.07 � 9.03 30.82 � 6.6 <0.001 45 � 8.50 37.93 � 14.55 0.04

Change �14.25 � 10.18 �7.05 � 11.27

*p-value for comparing within each group trend. Repeated-measure analysis of variance was used. †End–baseline. Values are expressed as mean � SD.

GI, gastrointestinal.



IBS-QoL significantly improved at the end of the study

in both groups (Table 5). As Table 5 indicates, a

significant improvement in the mean score changes

in dysphoria, health worries, food avoidance, social

reaction, relationships, and sexual subscales was seen

in the vitamin D group as compared to the control

group postintervention. The QoL improved signifi-

cantly in 25OHD3 deficient patients when compared

with the vitamin D replete ones (Fig. 3).

DISCUSSION

This study was designed to assess the effect of vitamin

D on patients with IBS in a randomized clinical trial.

The findings indicated that vitamin D supplement

therapy has beneficial effects on IBS-QoL and the IBS

severity score correlating with improved abdominal

pain and distention, flatulence, rumbling, and overall

GI symptoms as compared to the placebo group. No

significant differences were detected in dissatisfaction

with bowel habits between the vitamin D and placebo

groups.

A research on healthy humans suggested that doses

up to 10 000 IU per day are safe.25 In a recent study, we

provided evidence that giving 50 000 IU vitamin D

fortnightly improved serum 25(OH)D concentrations,

taking the fact into consideration that after 4 months

none of the treated patients were 25(OH)D deficient

(<20 ng/mL), and no adverse or side effects such as

hypercalcemia were reported.26 Based on the afore-

mentioned evidence, we decided to administer

50 000 IU vitamin D fortnightly to ensure that possi-

ble lack of effect could not be ascribed to suboptimal

serum 25(OH)D levels. To our best knowledge, this is

Figure 2 Gastrointestinal symptom’s score trend during intervention periods. Values are expressed as means with 95% CI. Repeated-measure

analysis of variance was used for the evolution of the symptoms score, either comparing each time points (*p < 0.007) or global evolution throughout

the 6-month period of the treatment (#p < 0.05), between vitamin D and placebo groups.

Figure 3 Mean score changes in IBSSS, IBS-QoL, and gastrointestinal

symptoms following 6-month vitamin D supplementation at

baseline in deficient and replete patients, *p < 0.05.



the first clinical trial that has assessed the effect of

vitamin D supplementation on IBS patients.

In the pathogenesis of IBS both central and periph-

eral factors have been implicated.15 It is evident that

the inflammatory response such as activated T lym-

phocytes, mast cells, and enhanced expression of pro-

inflammatory cytokines in IBS patients27 has an

important role in the induction of altered colonic

physiology generating the IBS symptoms.28 Histologi-

cal examination in humans demonstrated an increase

in mast cell, lymphocytes, and other cell types number

in some parts of the colon and small intestine of IBS

patients.15 In addition, inflammation leads to height-

ened nervous system sensitivity, which causes visceral

hypersensitivity and abdominal pain perception.4,29

Furthermore, psychological factors such as hypochon-

driasis, anxiety, and depression play an important role

in the onset and progress of IBS. Anxiety and

depression are common in IBS patients, and the

patients report a close relation between stress and

their bowel symptoms.4 In two thirds of IBS patients,

psychiatric illness or anxiety preceded the onset of

bowel symptoms, and most of the patients report that

stress leads to changes in stool pattern and acute

abdominal pain.4 Psychological treatment and treat-

ment of associated anxiety and depression often

improve gut and other symptoms such as pain percep-

tion.4

Previous studies have indicated that serum vitamin

D levels are correlated with depression and anxiety in

patients with fibromyalgia.17 Also, research has

demonstrated that lower vitamin D levels are seen in

people with depression as compared with their con-

trols,30 and supplementation with vitamin D could

improve the symptoms of depression.19 On the other

hand, vitamin D is potentially an immunomodulatory

Variables



IBS-QoL overall score

Baseline 60.51 � 9.50 59.05 � 11.55

6 months 74.77 � 8.7 70.01 � 11.25

Change‡ 14.26 � 3 <0.001 11 � 2.34 <0.001 <0.001Dysphoria

Baseline 58.52 � 21.65 58.54 � 23.60

6 months 72.43 � 21.30 69.34 � 20.53

Change 13.93 � 5.26 <0.001 10.80 � 5.83 <0.001 0.01

Interference with activity

Baseline 57.80 � 21.36 55.10 � 23.60

6 months 72.80 � 21.43 67 � 22.05

Change 15 � 7.01 <0.001 11.90 � 8.35 <0.001 0.07

Body image

Baseline 63.20 � 26.21 58.40 � 25.02

6 months 77.18 � 22.95 69.75 � 24

Change 14 � 9.93 <0.001 11.36 � 8.03 <0.001 0.2

Health worries

Baseline 51.30 � 27.81 55.17 � 23

6 months 65 � 25.53 65.71 � 20.77

Change 13.71 � 6.7 <0.001 10.53 � 4.20 <0.001 0.01

Food avoidance

Baseline 49.10 � 26.90 47.12 � 23.11

6 months 61.80 � 26.39 57.32 � 22.30

Change 12.70 � 4.40 <0.001 10.20 � 3 <0.001 0.003

Social reaction

Baseline 67 � 22.30 63.85 � 25.73

6 months 81.95 � 19.27 75.12 � 23.30

Change 14.95 � 8.62 <0.001 11.27 � 8 <0.001 0.04

Sexual

Baseline 69.43 � 24.55 68.44 � 26.91

6 months 85.10 � 14.45 79.46 � 21.66

Change 15.66 � 11.57 <0.001 11.02 � 8.06 <0.001 0.03

Relationships

Baseline 67.77 � 20.83 65.78 � 19.08

6 months 81.93 � 16.76 76.40 � 20.90

Change 14.16 � 9.10 <0.001 10.62 � 6.55 <0.001 0.04

*p-value for comparing the changes in variables between the groups. Two-sample t-test was

used. †p-value for comparing baseline with endpoint values within each group. Paired sample t-

test was used. ‡End–baseline. Values are expressed as mean � SD. IBS-QoL, IBS quality of life.



endpoint measures for IBS-QoL in vitamin D

and placebo groups



and anti-inflammatory factor which has been well

discussed in the literature.11,31–33 Hence, vitamin D

could improve psychological distress and low-grade

mucosal inflammation which can perturb the sensory–motor system of the gut, alter gut function, and cause

visceral hypersensitivity responsible for IBS symptoms.

In addition, vitamin D receptor is expressed in the gut

and throughout the nervous system, which regulates

epithelial barrier function, neurotransmitter levels,

and serotonin synthesis and also upregulates neu-

rotrophins.34–36 Thus, vitamin D may directly impact

gut function, neurological development, and IBS symp-

toms. When considered together, these processes may

underline the effectiveness of vitamin D in improve-

ment of IBS-QoL and symptoms, as reflected in the

results of this study.

As Table 4 shows, the biggest change in all symp-

toms scores belongs to abdominal pain (mean

change � SD: �16.81 � 11.03). It is well known that

enhanced pain sensitivity to experimental gut stimu-

lation is recognized as visceral hypersensitivity.4 Vis-

ceral hypersensitivity has an important role in the

development of chronic pain and discomfort in IBS

patients. A combination of factors involved in height-

ened sensitivity of both peripheral and central nervous

system causes visceral hypersensitivity.4 Mechanisms

which lead to enhanced nervous system sensitivity

have well been described in the models of inflamma-

tion.4 Indeed, Vitamin D could affect peripheral ner-

vous system by immunomodulatory and anti-

inflammatory actions and central nervous system by

antidepressant/anxiety effects, and could be effective

in improving the visceral hypersensitivity and abdom-

inal pain.

Vitamin D has shown beneficial effects on other GI

disorders like inflammatory bowel disease (IBD). Evi-

dence supported the hypothesis that the effect of

vitamin D on IBD pathogenesis is may be through

the anti-inflammatory effects of this vitamin.37 There

have been several studies examining the therapeutic

effect of vitamin D on animal models of IBD.38,39 In a

study on interleukin-10 knockout mice that sponta-

neously developed symptoms resembling human IBD,

1,25(OH)2D3 therapy for 2 weeks significantly amelio-

rated the symptoms of IBD.39 In 2009, Miheller et al.

assessed the therapeutic effects of 1,25(OH)2D3 and 25

(OH)D in Crohn’s disease (CD) patients with respect to

disease activity.40 There was a significant improve-

ment in disease activity after 6 weeks posttreatment

with 1,25(OH)2D3 but not with 25(OH)D3.40 In our

study, abdominal pain and distention, flatulence, and

overall GI symptom did not show any significant

improvements until the 4th month compared to the

controls. However, rumbling significantly improved at

5th and 6th month of study. As seen in Fig. 2,

50 000 IU vitamin D3 fortnightly was effective on IBS

symptoms in long-term supplement therapy starting at

4th month. This could possibly be due to the late

improvement of inflammation or psychological dis-

tress.19,41 Further investigations are needed to deter-

mine such a supposition.

In a pilot study on CD patients, 24-week vitamin D

supplementation, starting with 1000 IU/day and con-

tinuing up to 5000 IU/day effectively raised serum 25

(OH)D3 levels from 16 � 10 ng/mL to 45 � 19 ng/mL

(p < 0.0001) and significantly reduced the unadjusted

mean CD activity index scores.42 In our study, vitamin

D supplementation significantly increased the mean

serum 25(OH)D3 levels more than 2.5 times from the

baseline, and significantly reduced the mean IBSSS

score more than threefold in the treatment group. In

this study, about 65% of the participants had serum 25

(OH)D3 concentrations <20 ng/mL at the baseline

emphasizing the importance of vitamin D supplemen-

tation. Such a deficiency and related fractures in IBS

patients have been reported previously.13,14 Also, VDD

is common in other GI diseases such as IBD, celiac

disease, and gastric bypass surgery.12

As indicated previously, dietary restrictions such as

elimination of dietary source of fiber which is reported

in IBS patients could affect the bowel movements.43,44

Irritable bowel syndrome patients report that diet

affects their symptoms, and they often alter what they

eat to alleviate these symptoms.45,46 Our study found

no differences between the vitamin D and placebo

regarding the improvement of dissatisfaction with

bowel habits scores. The reasons for this result may,

partly, be due to the dietary restrictions and other

possible mechanisms not fully understood. Further

studies in this area will reveal more facts.

We also found that vitamin D could be effective in

the improvement of the QoL in IBS patients. Quality of

life is an important measure of the impact of IBS,

which is influenced by the depression status, appearing

with greater frequency in IBS patients.18 A research has

identified a strong statistically significant negative

correlation between the QoL score and both anxiety

and depression in these patients.47 As indicated in the

literature, vitamin D supplementation could amelio-

rate the symptoms of depression19 and, therefore, could

affect QoL. Moreover, the improvement of the IBS-QoL

might be through the improvement of IBS symptoms.

Our study is the first report on the effect of vitamin D

supplementation on IBS-QoL. Nevertheless, previous

studies on the patients with other chronic diseases

reported beneficial effect of vitamin D on improving



the QoL.42 A potential limitation of our study is that

psychological factors of the patients were not evalu-

ated.

As Fig. 3 shows, GI symptoms, IBSSS, and IBS-QoL

were highly enhanced in 25OHD3 deficient patients

than in the replete patients; nevertheless, it was not

significant regarding the GI symptoms and IBSSSS.

There was a significant difference in improvement of

IBS-QoL between the deficient and replete patients,

which emphasizes the beneficial effect of vitamin D

supplementation in 25OHD3 deficient patients.

A ‘placebo’ effect of 27% was observed in the

controls, which confirms the other placebo-Rando-

mized controlled trials on IBS subjects, showing an

average placebo response rate of 16–71%.48 Placebo

effect may have a significant impact on the interpre-

tation of RCTs. Kaptchuk et al. demonstrated that the

placebo effects produce significant improvement in

global improvement scale, adequate relief of symp-

toms, symptom severity score, and QoL.49 In our study,

all the symptoms, the IBSSS score, and the QoL

improved significantly in the placebo group as com-

pared to their baseline (Tables 3–5).In conclusion, this study indicates the beneficial

effects of 50 000 IU vitamin D3 fortnightly on IBS

symptoms, severity, and on patients’ QoL. Moreover,

supplementation with vitamin D3 could be effective in

a long-term course. Further studies are required to

provide additional evidence to support the use of

vitamin D to improve the IBS symptoms, severity,

and QoL in clinical settings.

ACKNOWLEDGMENTS

We are sincerely grateful to Mrs. Razieh Choghakhori for herexcellent collection and management of data.

FUNDING

This work was a part of PhD thesis of Amir Abbasnezhad and wasfinancially supported by a grant (no. NRC-9410) from the ViceChancellor for Research at the Jundishapur University of MedicalSciences and approved by the Nutrition and Metabolic DiseasesResearch Center, Jundishapur University of Medical Sciences,Ahvaz, Iran.

CONFLICTS OF INTEREST

The authors have no competing interests.

AUTHOR CONTRIBUTION

AA is the guarantor of the manuscript; AA, RA, and EH providedthe overall concept and framework for the manuscript, andinvolved in the drafting and critical revision of the manuscript;RA supervised the research; PA served as Medical Expert; AGserved as the coordinating investigator; BC was responsible for thestatistical analyses. All authors contributed to data interpretationand critically reviewed the manuscript and approved the finalversion of the manuscript, including the authorship list.

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