Karimi et al.

Nutrition Journal (2019) 18:16

https://doi.org/10.1186/s12937-019-0441-7

RESEARCH Open Access

The effects of two vitamin D regimens on

ulcerative colitis activity index, quality of life
and oxidant/anti-oxidant status
Sara Karimi1, Sanam Tabataba-vakili2, Zahra Yari1, Forough Alborzi3, Mehdi Hedayati4, Nasser Ebrahimi-Daryani3 and
Azita Hekmatdoost1*

Abstract
Background: The optimum dosage for vitamin D supplementation has not yet been elucidated in patients with
Ulcerative colitis (UC). The aim of this study was to investigate the effects of two vitamin D regimens in UC patients
with vitamin D deficiency.
Methods: In this double blind randomized clinical trial, 50 patients with mild to moderate UC, who met inclusion
criteria, received either 1000 or 2000 IU/day of vitamin D (as low dose or high dose group, respectively) for 12 weeks.
Serum 25-hydroxy vitamin D (25-OHD) level, total antioxidant capacity (TAC), and Total Oxidant Status (TOS), the
inflammatory bowel disease questionnaire − 9 (IBDQ-9) score and the Simple Clinical Colitis Activity Index Questionnaire
(SCCAI) score were assessed before and after intervention.
Results: At the end of study, serum 25-OHD levels significantly increased in the high dose group (P < 0.001) and the
increase was significantly more than low dose group (6.7 ± 3.8 ng/mL in the high dose group versus 0.2 ± 0.5 ng/mL in
the low dose group) (P < 0.001). Serum TOS concentration decreased significantly (− 0.37 ± 0.26) only in the high dose
group (P value = 0.023). There was no statistically significant change in serum TAC between two groups during the
study. IBDQ-9 mean score significantly increased in high dose group compared to the low dose group (P value = 0.001)
and SCCAI score in both groups reduced (− 2.58 ± 2.16 and − 0.9 ± 0.3 in high dose and low dose respectively), while
this reduction was significant only in the high dose group (P value ≥0.001).
Conclusion: Our results indicate that 2000 IU daily dose of vitamin D can increase serum 25-OHD concentration, and
quality of life, while it reduces disease activity in UC patients with vitamin D deficiency. We recommend assessment of
the vitamin D status in all patients with UC because they may benefit from vitamin D therapy.
Keywords: Ulcerative colitis, Inflammatory bowel disease, Vitamin D, Oxidative stress

Introduction The incidence and prevalence of IBD is increasing over

Inflammatory bowel disease (IBD) is a type of immune-me- time in western countries and in different parts of the
diated chronic bowel disorder including Ulcerative colitis world [9]. The prevalence of UC in Europe and North
(UC) and Crohn’s disease (CD) [1]. The etiology of IBD is America has been reported to be 505 and 249 out of
not completely understood; however, increasing evidence every 100,000 persons, respectively [10]. Although little
have shown the role of genetic and environmental factors epidemiological information of developing countries is
on immunopathologic processes of disease [2–8]. available, recent studies indicate that this disease is rap-
idly increasing in many developing countries as well as
Africa, South America and Asia [9–11]. In spite of signifi-
cant advances in the treatment of this disease, no definitive
* Correspondence: [email protected]
1
Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences
treatment has yet been found so far and the aim of existing
and Food Technology, National Nutrition and Food Technology, Research treatments is to reduce symptoms, prolongation of disease
Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran remission and improvement in patients’ quality of life.
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Karimi et al. Nutrition Journal (2019) 18:16 Page 2 of 8

These medications have serious side effects such as in- Thus, we designed this study to determine the effects of
creasing the risk of infection, increasing the sensitivity and two dosages of vitamin D supplementation on serum vita-
risk of mutagenesis, which limits their therapeutic value min D, total antioxidant capacity (TAC), total oxidant
[1, 12–14]. status (TOS), quality of life, and disease activity index in
Vitamin D has been linked to a wide range of physio- patients with UC.
logical functions including immune responses [15]. Vita-
min D deficiency has been associated with various Materials and methods
immunological diseases such as allergies and auto- Study design
immune diseases. Different mechanisms for the effects of This study is a double blind randomized clinical trial,
vitamin D on inherent and acquired immune systems are which included patients with mild to moderate UC [14]
supposed to reduce inflammation, promote immuno- referring to Shahid Fayyaz-Bakhsh Hospital, and a private
logical tolerance, and increase the intestinal epithelial gastroenterology clinic, who fulfilled the inclusion criteria
integrity [16]. of the study. At the beginning of the study, the goals and
Several studies have been conducted to evaluate the effi- methods of the study were explained to patients. Out of
cacy of vitamin D in IBD patients and in some of them a 77 patients, 65 UC patients were interviewed and 50
link between vitamin D deficiency and disease activity, patients were willing to take part in our study (Fig. 1).
mortality and severity of the disease, its early onset and risk Written consent approved by the ethics committee of the
of recurrence was found [17–22]; however, the optimum National Nutrition and Food Technology Research Insti-
dosage for supplementation has not yet been elucidated. tute (NNFTRI), Shahid Beheshti University of Medical

Fig. 1 Patients’ recruitment flow chart

Karimi et al. Nutrition Journal (2019) 18:16 Page 3 of 8

Sciences (SBMU), Tehran, Iran, was obtained from all pa- patient’s unwillingness to continue study protocol, changes
tients. A general demographic questionnaire was com- in the type and dosage of the drug during the study.
pleted for each patient. Meanwhile, the inflammatory
bowel disease questionnaire-9 (IBDQ-9) and the Simple
Clinical Colitis Activity Index Questionnaire (SCCAIQ) Interventions
were completed. [14]. The IBDQ-9 questionnaire was de- In this study, participants were randomly divided into
signed by Casellas et al. [23]. To measure the quality of life two groups to receive either a high-dose or a low-dose
affected by IBD from the original IBD questionnaire. This vitamin D supplement. Patients received the supple-
questionnaire contains 9 questions, which like the original ments for 12 weeks [14, 25], based on their group assign-
version, assesses the condition from the four dimensions ment. Participants in high dose group, received 2
of gastrointestinal, systemic, emotional and social distur- capsules of 1000 IU vitamin D daily [25]. Patients in the
bances. The answer to each question has 7 choices that low dose group were given 1 capsule of 1000 IU of vita-
range from 1 (the worst) to 7 (the best). The patient should min D supplements and 1 capsule of placebo daily,
mark one of the options as the best answer for each ques- which were apparently similar to each other. Supplement
tion, and the total score is 9 to 63. The higher score repre- capsules were purchased from Zahravi Company. For
sents a better quality of life in patients. It is worth noting blinding the study supplements, the boxes containing
that this questionnaire has been linguistically validated for the capsules were coded as A, B and C, by a person
Iranian patients [24]. SCCAI-Q which is suitable for evalu- other than the researchers. All of the patients received a
ation of patients with UC is a clinical activity indicator and box of A, but according to the fact that patients in the
consists of 6 questions, scaled from zero to 18. group receiving a high or a low dose of vitamin D sup-
In order to evaluate patients’ dietary intakes, three 24-h plementation, boxes B or C were given to them, as vita-
food recalls on one holiday and two working days were min D or placebo capsules. Therefore, patients received
completed through telephone or in-person interviews at 2000 IU vitamin D or 1000 IU vitmin D plus a placebo
the beginning and end of study. Patients were asked not capsule. Patients’ compliance was assessed using
to change their diet and physical activity during the study capsules count remained in the box at each visit (6th,
period. The analysis of 24-h food recall questionnaires and 12th week of the intervention).
was done using Nutritionist IV (N4) (First Databank,
Hearst Corp, San Bruno, CA, USA). Measurements
At first, and 12th week of study, the weight of each patient
Ethical considerations was measured in light weight clothing, with accuracy of
This study was conducted in accordance with principles 100 g and height measurement of each patient without
of the medical ethics committee of National Nutrition shoes was performed by meters mounted on a wall with a
and Food Technology Research Institute, No.1395.110, 1 cm accuracy. Then the body mass index (BMI) was cal-
and has been registered at the Iranian Center for Clinical culated. After 9–12 h of fasting, 5 cc blood samples were
Trials (No. IRCT 20100524004010 N22). taken from each patient and their serum was kept in the
− 80°c freezer until serum measurement analysis.
Study participants IBDQ-9 and SCCAIQ were filled out at the beginning
Patients with active mild to moderate UC, whose disease and the end of study. Serum concentrations of TAC,
had been confirmed pathologically, were recruited for TOS and 25- hydroxyl vitamin D (25-OHD) concentra-
this study. The inclusion criteria included: histopathologic tion were measured using ELISA method (ZellBio
diagnosis of mild to moderate (diagnosis of the severity of GmbH, Ulm, Germany) [14, 23, 26, 27].
the disease was based on physician’s judgment), vitamin D
deficiency (< 30 ng/mL), the absence of other diseases,
intestinal disorders, known autoimmune diseases, cancer, Statistical analysis
inflammatory and infectious diseases, not using vitamin D Data are presented as (mean ± standard deviation) and
supplements, mineral-multivitamins, omega-3, poly- frequency (percentages) for quantitative and qualitative
phenolic and antioxidant medications, and not using of an- variables, respectively. Normal distribution of data was
ticoagulants such as Heparin and Warfarin, non-steroid evaluated using Kolmogorov-Smirnov test. Chi-Square
anti-inflammatory drugs such as Ibuprofen, Aspirin and test was used to compare the qualitative confounding
Diclofenac, Antihistamines and calcium channel antago- variables of the two groups. To compare the mean of
nists such as Nifedipine during the past month, age > 18, quantitative variables in each group (if their distribution
and no change in the type and dosage of their medicine was normal) paired t-test was used for double-measured
over the past month. The exclusion criteria included preg- data and comparison of their mean between two groups
nancy or breastfeeding or using contraceptives in women, was evaluated by Student’s t-test.
Karimi et al. Nutrition Journal (2019) 18:16 Page 4 of 8

Results Table 2 Body mass index and medications in patients

Fifty patients (25 in the high dose group and 25 in participated in two groups receiving high and low doses of
the low dose group) took part in our study. A total vitamin D in the beginning and the end of the study *
of 46 patients, including 24 patients in the high dose Variables Time of the study P-
valuea
group (52.2%) and the 22 patients in the low dose Beginning of study End of study
group (47.8%) completed the study and 4 patients lost Body mass index (kg/m2)
to follow-up; the reasons for the withdrawal of pa- High dose group 24.29 ± 3.61 24.69 ± 3.34 0.087
tients from both groups are shown in Fig. 1. There
Low dose group 25.56 ± 4.27 25.69 ± 4.39 0.192
was no significant difference in the dropout rate
P-valueb 0.284 0.382
between two groups (P-value = 0.609). In general, the
participation rate in this study was 92%. Dose of Azathioprine (mg/day)
As shown in Table 1, there was no significant dif- High dose group 87.50 ± 25 87.50 ± 25 1
ference in the distribution of sex as well as age and Low dose group 83.33 ± 35.35 83.33 ± 35.55 1
length of the disease between high dose and low dose P-valueb 0.837 0.837
group at the beginning of the study (Table 1). Com-
Dose of Corticosteroid (mg/day)
parison of BMI and medications during the study did
High dose group 2.5 ± 7.3 0.9 ± 2.5 0.16
not show any significant difference in each group
(Table 2). All patients used Masalamine at the begin- Low dose group 0.2 ± 1.0 0 0.32
ning and the end of study. Forty one percent of par- P-valueb 0.16 0.10
ticipants in low dose group and 16.6% in high dose Dose of Mesalamine (mg/day)
group took Azathioprine (p = 0.55). Corticosteroids High dose group 2473.68 ± 1123.90 2450 ± 1099.04 0.331
were used by 12.5, and 13.6% of patients in high dose
Low dose group 2523.81 ± 872.87 2523.81 ± 872.87 0.696
and low dose groups, respectively (p = 1). Moreover,
P-valueb 0.875 0.813
there was no significant difference between the two
* Values are reported as Mean ± standard deviation
groups in terms of calorie intake and dietary a
within groups; b between groups
components.
Serum 25-OHD level was not significantly different low dose group (Table 3). The mean changes in low
between two groups at the beginning (p = 0.37), and dose and high dose groups were 0.2 ± 2.2 and 6.7 ±
the end of study (p = 0.93). In the high dose group, 3.8 respectively, which was significantly higher in
serum 25-OHD significantly increased during the high dose group compared with low dose group (p <
study, while this increase was not significant in the 0.0001).

Table 1 The duration of the disease and individual characteristics of the patients participated in two groups receiving high and low
doses of vitamin D before intervention *
Variables Low dose group High dose group P-value
N = 22 N = 24
Gender (n(%)) 1a
Men 11 (50) 13 (54.2)
Women 11 (50) 11 (45.8)
Age (years) 39.72 ± 15.56 34 ± 12.48 0.174b
Men 35.00 ± 14.89 33.31 ± 14.62 0.782b**
Women 44.45 ± 15.41 34.82 ± 10.02 0.098b**
Duration of disease (years) 7.18 ± 1.15 4.04 ± 0.97 0.083b
Men 6.18 ± 2.18 4.07 ± 1.39 0.408b**
Women 8.18 ± 2.15 4.01 ± 1.42 0.122b**
Extension of Disease (n (%)) 0.97a
Proctitis 7 (32) 7 (30)
Left side 14 (63) 16 (66)
Pancolitis 1 (4) 1 (4)
*The values for age and duration of the disease are reported as mean ± SD and the others reported as number (percentages)
**
Variables test between the two groups separated by gender
a
Fisher’s Exact Test
b
Student’s t-test
Karimi et al. Nutrition Journal (2019) 18:16 Page 5 of 8

Table 3 Mean and standard deviation of vitamin D levels in Discussion

patients participated in two groups taking high and low doses To our knowledge, this study is the first double blind
of vitamin D at the beginning and end of the study* randomized clinical trial in adult patients with UC,
Variables Time of the study P- which has assessed the effects of two dosages of vitamin
valuea
Beginning of study End of study D supplementation on its serum concentration, disease
Serum 25-hydroxy vitamin D (ng/mL) activity index, quality of life and body oxidative stress
High dose group 21.83 ± 9.69 28.99 ± 8.69 < 0.001 status. Our results have shown that daily dose of 2000
IU vitamin D increases 25-OHD level significantly; how-
Low dose group 24.37 ± 8.14 28.75 ± 11.90 0.192
ever, this result in daily dose of 1000 IU was not
P-valueb 0.377 0.936
observed. Based on the recommended dietary allowance
* Values are reported as Mean ± standard deviation
a
within groups; b between groups
(RDA), the daily requirement dosage of vitamin D in
adults (> 18 years) is 600 IU [28] but a recommendation
Serum concentrations of TOS and TAC, oxidant/anti- for supplementing vitamin D in IBD patients is not
oxidant concentrations did not change significantly in available. Some studies have shown that vitamin D
any of the two groups during the study. bioavailability decreases in patients with IBD; however, it
In the high dose group, serum TOS concentration in- is completely variable in different patients [29, 30]. In
creased significantly (P = 0.023) compared to the low addition to vitamin D malabsorption, inadequate ex-
dose group; however, this significance was eliminated posure to sunlight either related to lifestyle or persist-
after adjusting for confounders (P = 0.514). The change ent symptoms of active disease restricting physical
in serum TAC concentration between two groups during activity, inadequate dietary intake due to symptoms of
the study was not statistically significant and remained IBD, impaired conversion of vitamin D to its active
unchanged after adjusting for confounders (Table 4). products, increased catabolism and excretion are
As shown in Table 5, the mean score of IBDQ-9 after among high vitamin D deficiency prevalence in
vitamin D supplementation significantly increased in patients with IBD [31, 32].
both groups compared to baseline value. In the high Regarding malabsorption experienced by UC patients,
dose group, the IBDQ-9 mean score showed a significant we considered a higher level of vitamin D (2000 IU) as
increase compared to the low dose group (P value = their daily required dosage [33]. Also, to provide the low
0.001), which remained significant after adjusting for dose group sufficient amount of vitamin D, they were
confounding factors (p = 0.003). The SCCAI score in given a daily dose of 1000 IU.
both high dose and low dose groups was reduced at the Limited studies have evaluated the effects of vitamin D
end of the study compared to the beginning of the supplementation on its serum concentration in pediatric
study (P = 0.009, and p ≥ 0.001, respectively). In the patients with IBD. Simek et al [34] evaluated the effects
high dose group, the SCCAI mean scores in compari- of two dosages of 5000 IU of vitamin D3 per 10 kg of
son with the low dose group showed a significant body weight per week and 10,000 IU of vitamin D3 per
decrease (P = 0.004), which remained significant after 10 kg of body weight per week for a total of 6 weeks in
adjustment for confounders (p = 0.045). pediatric IBD patients. The concentration of this vitamin

Table 4 Mean and standard deviation of serum total oxidative and anti-oxidative capacity in patients participated in two groups
taking high and low doses of vitamin Dat the beginning and end of the study
Variables Time of the study
Beginning of study End of study P-valuec P-value
a b
P-value
Serum TOS (ng/mL) 0.023 0.514
Low dose group 2.94 ± 1.05 3.03 ± 0.80 0.70
High dose group 3.37 ± 0.96 2.99 ± 1.00 0.17
P-value d 0.15 0.90
Serum TAC (pg/mL) 0.209 0.599
Low dose group 0.57 ± 0.11 0.56 ± 0.12 0.47
High dose group 0.57 ± 0.13 0.56 ± 0.09 0.30
P-value d
0.93 0.86
The values are reported as mean ± standard deviation
a
P –value for complementary efficacy (changes comparison) by Student T-test
b
P-value for complementary efficacy (changes comparison) after adjustment by ANCOVA test for BMI, and baseline values
c
P –value for within group comparison using paired t test
d
P –value for between groups comparison using Student T-test
Karimi et al. Nutrition Journal (2019) 18:16 Page 6 of 8

Table 5 Mean and standard deviation score of quality of life and clinical activity score in patients participated in two groups taking
high and low doses of vitamin D at the beginning and end of the study
Variables Time of the study
Beginning of study End of study P-valuec P-value
a b
P-value
Quality of life questionnaire score 0.001 0.003
Low dose group 42.59 ± 8.66 44.73 ± 8.01 < 0.001
High dose group 40.54 ± 9.46 46.75 ± 9.27 < 0.001
P-valued 0.45 0.43
Clinical Activity Indicator Questionnaire score 0.004 0.045
Low dose group 3.00 ± 3.59 2.68 ± 2.27 0.009
High dose group 5.25 ± 2.98 2.67 ± 2.25 < 0.001
P-valued 0.06 0.98
The values are reported as mean ± standard deviation
a
P –value for complementary efficacy (changes comparison) by Student T-test
b
P-value for complementary efficacy (changes comparison) after adjustment by ANCOVA test for BMI, and baseline values
c
P –value for within group comparison using paired t test
d
P –value for between groups comparison using Student T-test

in both groups increased compared to the beginning of of vitamin D on the inherent and acquired immune sys-
the study at weeks 8 and 12.Papa et al. [25] evaluated tem are intended to reduce inflammation, promote
the effects of daily dose of 2000 IU vitamin D2(control), immune tolerance, and increase the integrity of the in-
and daily dose of 2000 IU vitamin D3 and weekly dose testinal epithelium [16]. Vitamin D is involved in the
of 50′000 IU vitamin D2 in pediatric patients with IBD. regulation of the immune system and may play a pivotal
Their results showed that oral doses of 2000 IU vitamin role in the pathogenesis of IBD and it is considered as a
D3 daily and 50,000 IU of vitamin D3 per week were su- contributing factor in the treatment of IBD [25].
perior to daily dose of 2000 IU vitamin D2 and were Our results showed that daily dose of vitamin D does
better tolerated in children and adolescents with IBD. not have any significant effect on oxidative stress status.
Moreover, our results showed that both doses of vita- Vitamin D plays an important role in a wide range of
min D improved patients’ quality of life; however, level physiological functions including immune responses
of disease activity only reduced by daily dose of 2000 IU. [15]. Vitamin D inhibits several pro-inflammatory path-
Although no clinical trial has reported the effects of vita- ways [37, 38], modifies autophagy [38], reduces the oxi-
min D on disease activity and patients’ quality of life, the dative stress [39], the differentiation and activation of
results of cross-sectional studies showed that the clinical the white blood cells [38, 40, 41] and increases the
activity and quality of life of IBD patients had a signifi- expression of tight junctions in the intestinal epithe-
cant relationship with lower levels of vitamin D [20, 35]. lium, thereby affecting mucosal permeability and tissue
A South African cohort study on Crohn’s disease found integrity [42].
a relation between low levels of vitamin D and increased Based on experimental studies, vitamin D receptor
activity of the disease [19]. In two other studies, it has (VDR) and its ligands have an important effect on IBD
been shown that low levels of vitamin D are common in disease [43]. Cantorna et al. [44] reported that mice with
IBD patients, which has been associated with mortality both vitamin D and IL-10 deficiency showed more acute
and severity of the disease as well as the early onset of entero-colitis at their 7th week of life. These authors
it, which could indicate the importance of the role of reported that VDR plays an important role in capacity of
this vitamin in the improvement of these patients [19, colonic epithelium healing.
22]. Another study showed that levels of 35 ng/mL or Wang et al. [45] showed that vitamin D deficiency ex-
less of serum vitamin D during the treatment period acerbates oxidative stress in obese patients. Vitamin D
would increase the risk of recurrence of UC [21]. plays an anti-oxidative role through the regulation of
Although previous studies have shown that high oxidative stress reducing proteins [46, 47]. In this study,
levels of vitamin D is associated with low frequency the primary level of oxidative stress was low, and this
of relapses [36], it is not known that blood vitamin D might be the reason of not observing a significant effect
affects the disease relapse, or disease activity affects of vitamin D on oxidant and antioxidant concentrations.
vitamin D status? The strength of the current study is evaluation of the
Vitamin D deficiency is associated with various effects of two doses of vitamin D supplements on serum
immunological diseases, such as allergies and auto- 25-OHD levels, oxidative factors, quality of life, and
immune diseases. Different mechanisms for the effects disease activity index in adult patients with active mild
Karimi et al. Nutrition Journal (2019) 18:16 Page 7 of 8

to moderate UC as the first double-blind randomized Author details

1
clinical trial. Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences
and Food Technology, National Nutrition and Food Technology, Research
Our study has some limitations. It may be necessary to Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
use vitamin D for a longer time or in higher doses in 2
Department of Medicine, Shahid Beheshti University of Medical Sciences,
order to observe its effects on oxidative stress status. Tehran, Iran. 3Division of Gastroenterology, Imam Khomeini Hospital, School
of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 4Cellular and
Another limitation of our study was the lack of a healthy Molecular Endocrine Research Center, Research Institute for Endocrine
control group to compare the results with the healthy Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
individuals. Moreover, we did not measure systemic
Received: 18 December 2018 Accepted: 4 March 2019
phlogosis markers in this study; however, we assessed
the oxidative stress status and disease activity which are
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SK and AH developed the proposal, obtained ethical approvals, applied for
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