Complementary Therapies in Medicine 63 (2021) 102787

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Complementary Therapies in Medicine

journal homepage: www.elsevier.com/locate/ctim

Administration of dietary antioxidants for patients with inflammatory

bowel disease: A systematic review and meta-analysis of randomized
controlled clinical trials
Hossein Shahinfar a, b, Nastaran Payandeh b, c, Maryam ElhamKia b, c, Fatemeh Abbasi b, d,
Alireza Alaghi b, e, Farhang Djafari b, c, Masoumeh Eslahi b, f, Narjes Sadat Farizani Gohari b, g,
Parivash Ghorbaninejad b, c, Mohaddeseh Hasanzadeh b, c, Alireza Jafari b, c, Aliyu Tijani Jibril b, c,
Reihane Khorasaniha b, c, Elahe Mansouri b, c, Vahid Monfared b, h, Soroush Rezaee b, c,
Adel Salehian b, h, Mahshid Shahavandi b, c, Leila Sheikhi b, i, Alireza Milajerdi b, f, *
a
Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
b
Nutritional Health Team (NHT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
c
Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
d
Department of sport injuries, Faculty of physical education and sport sciences, Allameh Tabataba’i University, Tehran, Iran
e
Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
f
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
g
Student Research Committee, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
h
Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran
i
Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: Accumulating evidence has been reported regarding the effect of dietary antioxidants on clinical
Antioxidants variables in IBD patients, however, findings are controversial. This systematic review and meta-analysis aimed to
Inflammatory bowel disease investigate effect of dietary antioxidants on clinical variables in patients with IBD or its subtypes.
Clinical remission
Methods: We searched PubMed, Scopus, and ISI Web of Science from inception to January 2021 using relevant
Endoscopic remission
Meta-analysis
keywords. Data were pooled by using the random-effect model. All statistical analyses were done using STATA
Randomized clinical trial version 14.
Results: Our meta-analysis was exclusively done on studies about the effect of curcumin on IBD patients, because
limited studies were done on other antioxidants. Curcumin administration resulted in significant increment of
clinical remission in patients with IBD (SMD: 0.86%, 95% CI: 0.16, 1.56, p = 0.016), significant remission in
clinical symptoms (SMD: − 0.96 score, 95% CI: − 1.34, − 0.57, p < 0.001), and significant increment in endo­
scopic remission in IBD patients (SMD: 0.51%, 95% CI: 0.16, 0.85, p = 0.004), comparing to control group.
Curcumin supplementation also made better clinical response than control group (SMD: 0.74%, 95% CI: 0.22,
1.26, p = 0.005) and also resulted in significant improvement in quality of life of patients with IBD, as compared
to control group (SMD: 1.23 score, 95% CI: 0.72, 1.74, p < 0.001).
Conclusions: Our meta-analysis showed that curcumin significantly improved clinical and endoscopic remissions
in IBD patients. This supplementation also caused significant reduction in clinical symptoms of IBD patients
along with better clinical response and the increased quality of life. Further researches with larger sample size
and longer period of intervention are required to evaluate efficacy of dietary antioxidants on clinical variables in
patients with IBD.

* Corresponding author at: Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical
Sciences, Kashan, Iran.
E-mail address: [email protected] (A. Milajerdi).

https://doi.org/10.1016/j.ctim.2021.102787
Received 8 July 2021; Received in revised form 25 October 2021; Accepted 28 October 2021
Available online 29 October 2021
0965-2299/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
H. Shahinfar et al. Complementary Therapies in Medicine 63 (2021) 102787

1. Introduction using MESH and non-MESH terms including ("RCT"[tiab] OR "random­

ized clinical trial"[tiab] OR "clinical trials as topic"[MeSH] OR "tri­
Inflammatory bowel disease (IBD) is an idiopathic intestinal in­ al*"[tiab] AND "curcumin"[MeSH] OR "curcumin"[tiab] OR
flammatory disease which includes two main subtypes including ulcer­ "curcuma"[tiab] OR OR "Resveratrol"[tiab] OR "Resveratrol"[MESH] OR
ative colitis (UC) and crohn’s disease (CD)1. The global prevalence of "antioxidants"[MeSH] OR "Antioxidant"[tiab] OR "Anti-Oxidant"[tiab]
IBD is increasing rapidly 2. IBD has several complications, which inter­ OR "vitamin C"[tiab] OR "vitamin E"[MESH] OR "vitamin E"[Title/Ab­
fere with a normal life of the suffering patients 3. In addition, it is a stract] OR "N acetylcysteine"[Title/Abstract] OR "Acetylcysteine"[­
known risk factor for many other chronic diseases 4,5. MeSH] OR "Acetylcysteine"[Title/Abstract] OR "ascorbic acid"[MeSH]
Exact etiology of IBD is unknown. However, it seems that inflam­ OR "ascorbic acid"[Title/Abstract] AND "Inflammatory bowel dis­
mation has a crucial role in the pathogenesis of this disease 6,7. ease"[Title/Abstract] OR "Inflammatory bowel diseases"[MeSH] OR
Administration of dietary antioxidants in patients with IBD resulted "Crohn disease"[Title/Abstract] OR "Crohn disease"[MeSH] OR "colitis,
controversial findings in previous studies8. Various treatments have ulcerative"[MeSH] OR "ulcerative colitis"[Title/Abstract] OR "IBD"[Ti­
been used by individuals to improve the condition of inflammatory tle/Abstract] OR "Crohn’s disease"[Title/Abstract]) No time and lan­
bowel disease9. For example, In Western countries, the use of comple­ guage restrictions were made. In addition, the reference lists of all
mentary and alternative drugs to improve chronic diseases increased included studies were manually searched to avoid missing any relevant
significantly in the 1990s and then reached a relatively constant level10. study. Grey literatures, including dissertations, letters, congress ab­
Some studies have also shown that supplementation with curcumin has stract, and etc. were removed.
been associated with the improvement in clinical outcomes, quality of
life, and inflammatory factors in UC patients in one study11 By
down-regulating inflammatory transcription factors such as NFkB, 2.2. Eligibility criteria
important enzymes such as cyclooxygenase 2 and 5 lipoxygenase and a
variety of cytokines such as tumor necrosis factor, interleukin 1 and Potentially relevant studies that met the following criteria were
interleukin 6 can have anti-inflammatory effects 12. Another study included: (a) original papers with either parallel or cross-over random­
showed that resveratrol supplementation improved quality of life and ized clinical trials (RCT) design; (b) studies conducted on individuals
simple clinical colitis activity index (SCCAI) in patients with UC13. aged 18 years old or more; (c) investigated the impact of oral supple­
However, the administration of oral curcumin at a dose of 450 mg/d in mentation with any dietary antioxidant on patients with IBD or its
another study had no significant influence on clinical remission of such subtypes, and (d) reported mean (SD) or percent changes or baseline and
patients14. These discrepancies might be due to the different dosages of final clinical remission rates, clinical response rates, endoscopic remis­
supplementation, and also differences in antioxidant type and admin­ sion simple clinical colitis activity index questionnaire (SCCAIQ) score,
istration routes. Although lower doses of curcumin (140 mg/day) were inflammatory bowel disease questionnaire-9 (IBDQ-9) score, SCCAI
used in Singla et al15. as compared to the Kedia et al. study 14 (450 score or other outcomes related to clinical symptoms of IBD patients in
mg/day), clinical findings were obviously better in patients with IBD. intervention and control group. If different articles were published on
The authors said that this finding might be partially explained by the data from the same population, we included only the most complete one.
different curcumin administration rout (enema vs. oral administration), Studies were excluded if they were reviews, meta-analyses, and
such that those received lower dose of curcumin via their enema had a ecologic studies, or if they were conducted on animals, pregnant or
better prognosis. In Singla et al. study despite lower dose of curcumin lactating women or children, or had no control group or studies assessed
comparing to other RCTs, they found a significant improvement in influence of antioxidant supplementation along with other in­
clinical remission and clinical responses of patients with IBD15. A recent terventions. We also excluded studies in which food items or herbs
meta-analysis of the effects of polyphenols on IBD showed that there is a containing antioxidants were used as the intervention.
significant association between curcumin supplementation and better
clinical response and endoscopic remission in patients with IBD 16. The 2.3. Data extraction
meta-analysis only included studies on supplementing curcumin.
Moreover, no subgroup analysis was done in that study. In addition, they Study selection and data extraction were performed at least twice by
used odds ratios to calculate final effect sizes, which might result in two independent researchers (HSH and NP). Any disagreement was
misleading conclusions for clinical trials in which two groups of inter­ discussed and resolved by a third reviewer (AM). Following data were
vention and control are comparing. collected from each study: study characteristics (first author’s name,
Although the results of early studies on the effects of dietary anti­ year of publication, study location, publishing year, and study design),
oxidants on the clinical symptoms of patients with IBD are controversial, participant characteristics (mean age and gender of participants sepa­
a comprehensive and conclusive study on this topic has not yet been rately by intervention and control group, health condition of partici­
conducted. The early meta-analysis only focused on a single dietary pants, and number of participants in each group), intervention (type,
antioxidant, and it also needs to be updated. Therefore, the current study dose, and duration of supplementation), mean and SD or percentage of
aims to systematically review existing randomized controlled trials on clinical variables at baseline, and end of study or changes between
the effects of dietary antioxidant supplementation on clinical variables baseline and post-intervention in both groups, and any adjustment for
in patients with IBD or its subtypes. confounding factors.

2. Methods
2.4. Quality assessment of included studies
The Preferred Reporting Items for Systematic Reviews and Meta-
analysis (PRISMA) guidelines were followed in conducting this sys­ The methodological quality of studies was assessed by using the
tematic review and meta-analysis 17. The PRISMA checklist has been Cochrane Collaboration risk of bias tool18. The following methodolog­
fulfilled for the current study (Appendix A). ical domains were considered: random sequence generation, allocation
concealment, blinding of participants and personnel, blinding of
2.1. Search strategy outcome assessment, incomplete outcome data, selective reporting, and
other potential threats to validity. According to Cochrane Handbook
Online medical databases, including PubMed, Scopus, and Web of recommendation, studies were stratified as low risk of bias, high risk of
Science were searched up to January 2021. Detailed search algorithm bias, or unclear regarding each domain.

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2.5. Statistical analysis results 20. Sensitivity analysis was done by excluding a single study in
each stage to find influence of each included study on overall results. All
Pooled effect sizes and corresponding 95% confidence interval (CI) analyses were undertaken using Stata software version 14 (Stata Corp.
were calculated using the mean changes and SDs of outcomes of interest College Station, Texas, USA). P-values less than 0.05 were considered to
in intervention comparing to control group. All analyses were done by be statistically significant.
the random-effect model. When means (±SD) of outcomes was not
directly available and a standard error of the mean (SEM) was presented, 3. Results
we converted it to SD using this formula: SD = SEM × √n, being “n” the
number of subjects in each group. If medians and inter-quartile range 3.1. Selected studies
were reported, mean and SD values were estimated using the method
described by Hozo et al19. Ultimately, we used the GetData Graph After searching databases, 316 relevant articles were included at the
Digitizer version 2.24 to extract data from studies that reported out­ initial stage. After removing duplicates, 211 relevant articles were
comes in the graphical form. We also converted all percentages to mean screened by title and abstract. After this stage, 31 articles remained for
and SDs for the current meta-analysis to made final results easy to read. the final evaluation. The full texts of the potentially eligible articles were
We assessed the magnitude of inter-study heterogeneity by the I2 sta­ retrieved for independent further screening. Finally, 12 articles were
tistics, where values greater than 50% were considered as evidence of included in the present systematic review. Of these articles, 7 studies
moderate to high between-study heterogeneity. A priori subgroup had information for meta-analysis. Fig. 1 demonstrates the process by
analysis by the predefined variables was performed to detect potential which articles were selected.
sources of heterogeneity. Any publication bias was investigated by
visually inspecting at funnel plots and quantitatively evaluated using the 3.2. Studies characteristics
Egger’s regression test. In case of detecting potential publication bias,
Duval & Tweedie “trim and fill” approach was applied to adjust final General characteristics of included studies have been summarized in

Fig. 1. Flow chart of the number of studies identified and selected into the meta-analysis.

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Table 1
Demographic characteristics of the included studies.

(continued on next page)

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Table 1 (continued )

(continued on next page)

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Table 1 (continued )

ITT: intention to treat; PP: per protocol; Int: intervention; Con: control; IU: international unit; UC: Ulcerative Colitis; CD: Crohn’s disease; vit: vitamin; mg: milligram; d:
day; a: after; b: before

Table 1. We identified 12 randomized controlled clinical trials (RCTs) plasma orosomucoid measurement was also taken to measure disease
that assessed effects of various antioxidant supplementation on activity. The plasma levels of vitamin C and alpha-tocopherol increased,
ameliorating symptoms of inflammatory bowel disease 13–15,21–31. These and virtually all indices of oxidative stress decreased during supple­
studies were carried out in various countries including Iran 13,27–30, mentation. Disease activity remained unchanged during supplementa­
India 14,15,22, Japan 24,25,31, Hong Kong 26 Canada 21, and France 23. tion. 21
Publication dates ranged from 2006 to 2020. Overall, 1060 participants Two studies reported the effect of resveratrol supplementation on
were enrolled in these studies. All RCTs were done on both genders and inflammation and oxidative stress status in patients with ulcerative co­
had parallel design. Different antioxidants including Curcumin, N-ace­ litis (UC). In study of Samsamikor et al. for 6 weeks, 56 patients with
tylcysteine, resveratrol, combination of vitamin C and E were used in our mild to moderate disease were randomly assigned to receive 500 mg/
included RCTs. Antioxidants were administrated through different day of resveratrol or an equivalent amount of placebo. Before and after
routes, including oral 13,14,21–31 and enema 15. Supplements were the intervention, disease activity, quality of life, and oxidative stress
administrated in doses ranging from 100 and 3000 mg/day. The inter­ were assessed using the Simple Clinical Colitis Activity Index Ques­
vention duration varied between 4 and 24 weeks. Most studies were tionnaire (SCCAIQ), Inflammatory Bowel Disease Questionnaire-9
conducted on patients with ulcerative colitis 13–15,21–24,26,27,29,30. (IBDQ-9), and serum level of malondialdehyde (MDA), superoxide dis­
However, a few papers enrolled patients with crohn’s disease 31. The mutase (SOD), and total antioxidant capacity (TAC), respectively. The
severity of disease in the patients was as follows: severe disease 27, results indicated that resveratrol supplementation significantly
mild-to-moderate 13–15,21–23,26,29–31, and Quiescent 24. RCTs had increased serum SOD, TAC, and quality of life and decreased serum MDA
analyzed effectiveness of antioxidants on these outcomes: clinical and disease activity 30. In another study investigated the effect of
remission 13–15,21,22,24,26,27,29–31, clinical response 15,22,26, endoscopic resveratrol supplementation on inflammatory biomarkers in patient
remission 14,15,22,23,26,31 and quality of life 13,23,29,30. Some studies had with ulcerative colitis. Six weeks of resveratrol or placebo supplemen­
adjusted for confounding factors 13,24,27,30, however, most of them did tation was given to 50 mild to moderately active UC patients. At baseline
not control for covariates 14,15,21–23,26,29,31. and the end of the study, serum inflammatory markers, NF-kB activity in
peripheral blood mononuclear cells (PBMC), and quality of life were
4. Quality assessment assessed. The results of resveratrol supplementation led to significant
reduction in plasma levels of TNF-α, hs-CRP, and NF-kB activity. The
All studies reported random allocation of participants 13–15,21–24,26, score of inflammatory bowel disease questionnaire -9 (IBDQ-9)
27,29–31
. Allocation concealment was reported in all papers 13–15,21–24,26, increased, whereas the clinical colitis activity index score decreased
27,29–31
. Low risk of bias in eight trials in terms of blinding of partici­ significantly in the resveratrol group.
pants, personnel, and outcome assessment was demonstrated 13,23,24,26, There was also one study that assessed the effect of N-acetylcysteine
27,29–31
and other 4 studies revealed high risk of bias 14,15,21,22. Ten (NAC) on remission maintenance in patients with ulcerative colitis by
studies indicated low risk of bias in domain of “incomplete outcome Masnadi Shirazi et al. They recruited 168 volunteers who were already
data” 13–15,21,22,24,27,29–31, while two other papers had high risk of bias taking high-dose corticosteroids and Mesalamine for flare-up manage­
23,26
. Eleven trials showed low risk of bias on selective outcome ment. These patients received either 800 mg of NAC or a placebo for 16
reporting 13–15,22–24,26,27,29–31 and only one research had unclear risk of weeks concurrently with tapering their prednisolone dose. The primary
bias 21. Details about risk of bias assessment are described in Table 2. efficacy of the treatment was remaining in remission. The secondary
outcomes were the endoscopic relapse, serum level of hs-CRP, hemo­
5. Systematic review globin, and fecal calprotectin level. In terms of the relapse-free period,
they showed NAC differed significantly from placebo. The mean fecal
The only RCT in this review evaluated the effect of antioxidant calprotectin, serum erythrocyte sedimentation rate, and hs-CRP levels
vitamin supplementation in patients with inactive or mildly active were significantly lower in the NAC group compared with the placebo
crohn’s disease. A total of 57 subjects were supplemented with vitamin E group. Also, they found NAC supplementation led to significant positive
(800 IU) and vitamin C (1000 mg) or their placebo for 4 weeks. A blood effect on the maintenance of remission in UC patients that were in ste­
test measuring breath pentane and ethane output, plasma lipid perox­ roid therapy 32.
ides and F2-isoprostane was analyzed at baseline and after four weeks. A

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Table 2
Cochrane risk of bias assessment.
Study Random Sequence Allocation Blinding of participants, personnel and Incomplete outcome Selective outcome Other
Generation concealment outcome assessors data reporting bias

Banerjee et al. 22 L L H L L U
Hanai et al. 24 L L L L L U
Kedia et al. 14 L L H L L L
Lang et al. 26 L L L H L U
Bommelaer et al. 23 L L L H L U
Masnadi Shirazi L L L L L U
et al. 27
Sugimoto et al. 31 L L L L L U
Sadeghi et al. 29 L L L L L H
Samsami-Kor et al. L L L L L U
13

Samsamikor et al. L L L L L U
30

Singla et al. 15 L L H L L L
21
Aghdassi et al. L L H L U U

L, low risk of bias; H, high risk of bias; U, unclear risk of bias

6. Meta-analysis analyses were conducted based on supplementation dosage and dura­

tion. Findings remained unchanged among all subgroups (Table 3).
6.1. Effect of curcumin supplementation on clinical remission
6.2. Effect of curcumin supplementation on endoscopic remission
A pooled analysis of seven papers that reported clinical remission in
percent, showed significant increment of clinical remission in patients
Combining six studies that evaluated endoscopic remission in pa­
with IBD (SMD: 0.86%, 95% CI: 0.16, 1.56, p = 0.016), with consider­
tients with IBD, we revealed that antioxidants supplementation signifi­
able heterogeneity (I2 = 90.4%; p < 0.001) (Fig. 2). This finding
cantly caused in the increased endoscopic remission in comparison to
remained unchanged in all subgroups, except for studies done on pa­
control group (SMD: 0.51%, 95% CI: 0.16, 0.85, p = 0.004) with mod­
tients with < 40 years old, in which no significant change was seen
erate heterogeneity (I2 = 52.0%; p = 0.064) (Fig. 3). Similar to clinical
(SMD: − 0.05%, 95% CI: − 0.33, 0.23, p = 0.741) (Table 3). Further­
remission, subgroup analysis showed no significant effect of antioxidant
more, two studies reported mean (SD) changes in clinical symptoms
only on those aged < 40 years (SMD: 0.19%, 95% CI: − 0.11, 0.49,
score following antioxidant supplementation in patients with IBD.
p = 0.224) (Table 3).
Pooling these studies, we found significant remission in clinical symp­
toms of IBD patients following antioxidants supplementation (SMD:
− 0.96 score, 95% CI: − 1.34, − 0.57, p < 0.001), with significant het­ 6.3. Effect of curcumin supplementation on clinical response
erogeneity between included studies (I2 = 96.7%; p < 0.001). Subgroup
Meta-analysis of three studies showed that antioxidants

Fig. 2. Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of curcumin supplementation on clinical remission.

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Table 3
Subgroup analysis of included randomized controlled trials in meta-analysis of the effect of antioxidants on clinical and endoscopic remission.
Group No. of trials SMD (95% CI) P value I2 (%) P-heterogeneity P for between subgroup heterogeneity

Clinical Remission
Population < 0.001
< 50 3 1.20 (0.79, 161) < 0.001 89.9 < 0.001
≥ 50 4 0.34 (0.09, 0.59) 0.007 90.1 < 0.001
Age < 0.001
< 40 3 -0.05 (− 0.33, 0.23) 0.741 61.0 0.077
≥ 40 4 1.37 (1.05, 1.69) < 0.001 80.3 0.002
Dose 0.211
< 1000 4 0.72 (0.40, 1.04) < 0.001 90.9 < 0.001
≥ 1000 3 0.45 (0.16, 0.73) 0.002 92.9 < 0.001
Duration 0.282
< 12 4 0.66 (0.39, 0.94) < 0.001 79.5 0.002
≥ 12 3 0.43 (0.09, 0.76) 0.013 95.7 < 0.001
Endoscopic Remission
Population 0.313
< 50 3 0.62 (0.25, 0.92) 0.001 25.6 0.261
≥ 50 3 0.38 (0.07, 0.68) 0.015 70.2 0.035
Age 0.003
< 40 3 0.19 (− 0.11, 0.49) 0.224 0.0 0.840
≥ 40 3 0.91 (0.54, 1.28) < 0.001 0.0 0.503
Dose 0.654
< 1000 4 0.43 (0.14, 0.73) 0.004 45.5 0.138
≥ 1000 2 0.54 (0.16, 0.93) 0.005 78.8 0.030
Duration 0.738
< 12 3 0.44 (0.12, 0.76) 0.007 67.0 0.048
≥ 12 3 0.52 (0.17, 0.86) 0.003 52.9 0.120

Abbreviations: N: number; CI, confidence interval; SMD: Standardize mean differences.

Fig. 3. Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of curcumin supplementation on endoscopic remission.

supplementation made better clinical response than control group compared to control group (SMD: 1.23 score, 95% CI: 0.72, 1.74,
(SMD: 0.74%, 95% CI: 0.22, 1.26, p = 0.005), with moderate hetero­ p < 0.001).
geneity (I2 = 56.2%; p = 0.102) (Fig. 4). Due to the limited number of
included studies, it was impossible to do any subgroup analysis. 7. Discussion

Current systematic reviews and meta-analysis showed that supple­

6.4. Effect of curcumin supplementation on quality of life menting with dietary antioxidants significantly reduced the clinical and
endoscopic symptoms of IBD patients. Antioxidants also lead to better
Pooling one study showed antioxidant supplementation resulted in clinical responses in patients with IBD. Moreover, we found that
significant improvement in quality of life of patients with IBD, as

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Fig. 4. Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of curcumin supplementation on clinical response.

antioxidants supplementation can improve the quality of life of patient inflammation 39–41. Adherence to a diet high in total fat, oleic acid,
with IBD. SAFA, total PUFA, trans fat, MUFA, and linoleic acid is associated with
Consistent with our results, supplementation with 500 mg of an increased risk of ulcerative colitis39. Some of the other most common
resveratrol per day in a randomized double-blind placebo-controlled risk factors for IBD are genetic factors, immune response disorders,
trial significantly improved the quality of life of patients with active mucosal barrier dysfunctions, and loss of immune tolerance to intestinal
mild to moderate UC 13. Some other studies reported that the use of flora 35,36,42,43. Increased production of inflammatory mediators
polyphenols can improve IBD-related complications 16,33–35. Another (including oxygen and nitrogen active substances, prostaglandins and
study by Samsami et al. showed that supplementation with resveratrol cytokines) can lead to uncontrolled inflammation in these patients 35.
for 6 weeks at a dose of 500 mg/day can significantly affect the disease Dietary antioxidants such as resveratrol reduce oxidative stress and
progression of UC patients and improve their quality of life 30. A through which might influence clinical responses in IBD patients. Di­
meta-analysis by Liu et al. in 2020 regarding the effect of polyphenols on etary antioxidants reduce neutrophil infiltration of intestinal mucosa,
IBD patients showed that polyphenols may be an effective supplemen­ inhibit TNF-α production and NF-κB activation 30,35. Inhibition of NF-κB,
tary treatment to improve clinical remission rate, endoscopic remission cyclooxygenase-2 44,45, TNF-α activities, and blockage of the JAK/STAT
rate and clinical response rate, especially in UC patients 16. However, pathway 46, along with up-regulation of IL-22 47,48 restrains inflamma­
other studies failed to find significant effect of antioxidants on clinical tory cascades in these patients. Reduction in inflammatory reactions will
and subclinical variables in patients with IBD. Although Sugimoto, et al. reduce frequency of attacks against gut mucosa. By this mechanism, we
study showed significant effects of a new and rapid derivative of cur­ will be able to explain why antioxidants might cause clinical and
cumin on clinical and endoscopic markers in patients with active endoscopic remission and finally increase the quality of life in patients
mild-to-moderate CD, no significant improvements were seen in sys­ with IBD. Significant reductions in endogenous production of lipid
temic biomarkers or quality of life of those patients 31. Studies have peroxides and reactive species of oxygen are other mechanisms through
shown that curcumin can regulate different cell signaling pathways, which antioxidants might reduce clinical problems in patients with IBD
which are important in prognosis of most chronic diseases12. However, 21
.
some studies in which low-dose (150 mg/day) oral curcumin was used Our meta-analysis has some advantages. To the best of our knowl­
for 8 weeks showed no significant effect on the clinical remission or edge, current study is the first comprehensive meta-analysis on the effect
response of patients with mild to moderate UC14. Differences in stages of of dietary antioxidants on clinical variables in patients with inflamma­
disease, disease types, and different dosages of various types of antiox­ tory bowel disease and its subtypes. Moreover, the literature search is so
idants may be the reasons for these discrepancies. Moreover, as we precise. However, we had sufficient data only for some specific types of
showed in our subgroup analyses, participants’ age might be a detri­ antioxidants to do meta-analysis. Moreover, we were not able to do our
mental factor for the effects of antioxidants on clinical and subclinical analyses separately for each type of antioxidants. We tried to solve this
variables in patients with IBD. Therefore, further researches are needed problem by subgroup analysis. In addition, different types of IBD,
to expand existing knowledge in this field. different dosages of the supplements, various study sample size and
Inflammatory bowel disease (IBD) is an idiopathic inflammatory duration were other concerns that needs to be investigated in further
bowel disease with multiple complications, and its global prevalence is trials. Lack of adjustment for important confounders was seen in most
rapidly increasing 36,37. In addition, IBD itself is also a known risk factor included studies. Furthermore, most included studies were done among
for many other chronic diseases 38. It is well known that the cause of IBD Eastern populations and more studies are required from other nations.
is unknown, but it seems that inflammation plays a crucial role in the Finally, current systematic review and meta-analysis was not registered
pathogenesis of this disease 36. High intake of dietary fats, obesity, and in a relevant database, because of time restrictions.
low intake of fruits and vegetables may be associated with elevated

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8. Conclusion 12. Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic
diseases: an age-old spice with modern targets. Trends Pharm Sci. 2009;30(2):85–94.
https://doi.org/10.1016/j.tips.2008.11.002 (Feb).
In summary, supplementation with antioxidants significantly 13. Samsami-Kor M, Daryani NE, Asl PR, Hekmatdoost A. Anti-inflammatory effects of
increased the clinical and endoscopic remissions in patients with IBD. resveratrol in patients with ulcerative colitis: a randomized, double-blind, placebo-
Antioxidants also improved the clinical responses in these patients and controlled pilot study. Arch Med Res. 2015;46(4):280–285. https://doi.org/
10.1016/j.arcmed.2015.05.005 (May).
improved their quality of life. More randomized clinical trials using 14. Kedia S, Bhatia V, Thareja S, et al. Low dose oral curcumin is not effective in
different types of antioxidants are required to shed light on this issue. induction of remission in mild to moderate ulcerative colitis: Results from a
randomized double blind placebo controlled trial. World J Gastrointest Pharm Ther.
2017;8(2):147–154. https://doi.org/10.4292/wjgpt.v8.i2.147 (May 6).
Funding source 15. Singla V, Pratap Mouli V, Garg SK, et al. Induction with NCB-02 (curcumin) enema
for mild-to-moderate distal ulcerative colitis - a randomized, placebo-controlled,
pilot study. J Crohns Colitis. 2014;8(3):208–214. https://doi.org/10.1016/j.
This research did not receive any specific grant from funding
crohns.2013.08.006 (Mar).
agencies in the public, commercial, or not-for-profit sectors. 16. Liu F, Li D, Wang X, Cui Y, Li X. Polyphenols intervention is an effective strategy to
ameliorate inflammatory bowel disease: a systematic review and meta-analysis. Int J
Food Sci Nutr. 2021;72(1):14–25. https://doi.org/10.1080/
CRediT authorship contribution statement 09637486.2020.1760220 (Feb).
17. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated
HSH and ARM designed the study. HSH, NP and ME did the literature guideline for reporting systematic reviews. Bmj. 2021;372:n71. https://doi.org/
10.1136/bmj.n71 (Mar 29).
search and screening data. HSH, ME, and NP performed data extraction 18. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for
and quality assessment, independently. AM, ME, NP and HSH analyzed assessing risk of bias in randomised trials. Bmj. 2011;343:d5928. https://doi.org/
and interpreted data and wrote the manuscript. AM edited and finalized 10.1136/bmj.d5928 (Oct 18).
19. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median,
the manuscript. AM supervised the study. All authors read and approved range, and the size of a sample. BMC Med Res Method. 2005;5(1):13.
the final manuscript. 20. Duval S, Tweedie R. Trim and fill: a simple funnel-plot–based method of testing and
adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–463.
21. Aghdassi E, Wendland BE, Steinhart AH, Wolman SL, Jeejeebhoy K, Allard JP.
Antioxidant vitamin supplementation in Crohn’s disease decreases oxidative stress.
Conflicts of interest statement
a randomized controlled trial. Am J Gastroenterol. 2003;98(2):348–353. https://doi.
org/10.1111/j.1572-0241.2003.07226.x (Feb).
The authors declared no conflicts of interest. 22. Banerjee R, Medaboina K, Boramma GG, Amsrala S, Reddy DN. Novel bio-enhanced
curcumin with mesalamine for induction of remission in mild to moderate ulcerative
colitis. Gastroenterology. 2017;152(5):S587.
Acknowledgments 23. Bommelaer G, Laharie D, Nancey S, et al. Oral curcumin no more effective than
placebo in preventing recurrence of Crohn’s disease after surgery in a randomized
controlled trial. Clin Gastroenterol Hepatol. 2020;18(7), 1553-1560.e1. https://doi.
None. org/10.1016/j.cgh.2019.08.041 (Jun).
24. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative
colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin
Appendix A. Supporting information
Gastroenterol Hepatol. 2006;4(12):1502–1506. https://doi.org/10.1016/j.
cgh.2006.08.008 (Dec).
Supplementary data associated with this article can be found in the 25. Itagaki M, Saruta M, Saijo H, et al. Efficacy of zinc-carnosine chelate compound,
online version at doi:10.1016/j.ctim.2021.102787. Polaprezinc, enemas in patients with ulcerative colitis. Scand J Gastroenterol. 2014;
49(2):164–172. https://doi.org/10.3109/00365521.2013.863963 (Feb).
26. Lang A, Salomon N, Wu JC, et al. Curcumin in combination with mesalamine
References induces remission in patients with mild-to-moderate ulcerative colitis in a
randomized controlled trial. Clin Gastroenterol Hepatol. 2015, 1444-9.e1. https://doi.
org/10.1016/j.cgh.2015.02.019 (Aug).
1. Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory
27. Masnadi Shirazi K, Sotoudeh S, Masnadi Shirazi A, Moaddab SY, Nourpanah Z,
bowel disease and colitis-associated colon cancer. Front Immunol. 2012;3:107.
Nikniaz Z. Effect of N-acetylcysteine on remission maintenance in patients with
https://doi.org/10.3389/fimmu.2012.00107.
ulcerative colitis: a randomized, double-blind controlled clinical trial. Clin Res
2. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of
Hepatol Gastroenterol. 2020. https://doi.org/10.1016/j.clinre.2020.08.010 (Oct 14).
inflammatory bowel disease in the 21st century: a systematic review of population-
28. Masoodi M, Mahdiabadi MA, Mokhtare M, et al. The efficacy of curcuminoids in
based studies. Lancet. 2017;390(10114):2769–2778. https://doi.org/10.1016/
improvement of ulcerative colitis symptoms and patients’ self-reported well-being: a
s0140-6736(17)32448-0 (Dec 23).
randomized double-blind controlled trial, 119(11): (2018);9552-9559. doi:10.1002/
3. Head KA, Jurenka JS. Inflammatory bowel disease Part 1: ulcerative colitis–
jcb.27273. (Nov).
pathophysiology and conventional and alternative treatment options. Alter Med Rev.
29. Sadeghi N, Mansoori A. The effect of curcumin supplementation on clinical
2003;8(3):247–283 (Aug).
outcomes and inflammatory markers in patients with ulcerative colitis. 2020;34(5):
4. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis.
1123–1133. https://doi.org/10.1002/ptr.6581 (May).
Lancet. 2017;389(10080):1756–1770. https://doi.org/10.1016/s0140-6736(16)
30. Samsamikor M, Daryani NE, Asl PR, Hekmatdoost A. Resveratrol supplementation
32126-2 (Apr 29).
and oxidative/anti-oxidative status in patients with ulcerative colitis: a randomized,
5. Gajendran M, Loganathan P, Catinella AP, Hashash JG. A comprehensive review and
double-blind, placebo-controlled pilot study. Arch Med Res. 2016;47(4):304–309.
update on Crohn’s disease. Dis Mon. 2018;64(2):20–57. https://doi.org/10.1016/j.
https://doi.org/10.1016/j.arcmed.2016.07.003 (May).
disamonth.2017.07.001 (Feb).
31. Sugimoto K, Ikeya K, Bamba S, et al. Highly bioavailable curcumin derivative
6. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology.
ameliorates Crohn’s disease symptoms: a randomized, double-blind, multicenter
1998;115(1):182–205. https://doi.org/10.1016/s0016-5085(98)70381-6 (Jul).
study. J Crohns Colitis. 2020. https://doi.org/10.1093/ecco-jcc/jjaa097 (May 15).
7. Sadeghi O, Milajerdi A, Siadat SD, et al. Effects of soy milk consumption on gut
32. Masnadi Shirazi K, Sotoudeh S, Masnadi Shirazi A, Moaddab SY, Nourpanah Z,
microbiota, inflammatory markers, and disease severity in patients with ulcerative
Nikniaz Z. Effect of N-acetylcysteine on remission maintenance in patients with
colitis: a study protocol for a randomized clinical trial. Trials. 2020;21(1):1–11.
ulcerative colitis: a randomized, double-blind controlled clinical trial. Clin Res
8. Ebrahimzadeh A, Abbasi F, Ebrahimzadeh A, Jibril AT, Milajerdi A. Effects of
Hepatol Gastroenterol. 2021;45(4), 101532. https://doi.org/10.1016/j.
curcumin supplementation on inflammatory biomarkers in patients with
clinre.2020.08.010 (Jul).
Rheumatoid Arthritis and Ulcerative colitis: a systematic review and meta-analysis.
33. Restellini S, Chazouillères O, Frossard JL. Hepatic manifestations of inflammatory
Complement Ther Med. 2021, 102773.
bowel diseases. Liver Int. 2017;37(4):475–489. https://doi.org/10.1111/liv.13265
9. Langhorst J, Wulfert H, Lauche R, et al. Systematic review of complementary and
(Apr).
alternative medicine treatments in inflammatory bowel diseases. J Crohns Colitis.
34. Walldorf J, Krummenerl A, Engler K, et al. Health care for osteoporosis in
2015;9(1):86–106. https://doi.org/10.1093/ecco-jcc/jju007 (Jan).
inflammatory bowel disease: unmet needs in care of male patients? J Crohns Colitis.
10. Okoro CA, Zhao G, Li C, Balluz LS. Has the use of complementary and alternative
2013;7(11):901–907. https://doi.org/10.1016/j.crohns.2012.12.008 (Dec).
medicine therapies by U.S. adults with chronic disease-related functional limitations
35. Nunes S, Danesi F, Del Rio D, Silva P. Resveratrol and inflammatory bowel disease:
changed from 2002 to 2007? J Alter Complement Med. 2013;19(3):217–223. https://
the evidence so far. Nutr Res Rev. 2018;31(1):85–97. https://doi.org/10.1017/
doi.org/10.1089/acm.2012.0009 (Mar).
s095442241700021x (Jun).
11. Sadeghi N, Mansoori A, Shayesteh A, Hashemi SJ. The effect of curcumin
36. Schmidt C, Stallmach A. Etiology and pathogenesis of inflammatory bowel disease.
supplementation on clinical outcomes and inflammatory markers in patients with
Minerva Gastroenterol Dietol. 2005;51(2):127–145 (Jun).
ulcerative colitis. Phytother Res. 2020;34(5):1123–1133. https://doi.org/10.1002/
ptr.6581 (May).

10
H. Shahinfar et al. Complementary Therapies in Medicine 63 (2021) 102787

37. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol patients with ulcerative colitis: study protocol for a randomized controlled trial.
Hepatol. 2015;12(12):720–727. https://doi.org/10.1038/nrgastro.2015.150 (Dec). Trials. 2020;21(1):1–7.
38. Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways 44. Jobin C, Bradham CA, Russo MP, et al. Curcumin blocks cytokine-mediated NF-
with other diseases. Gut. 2011;60(12):1739–1753. https://doi.org/10.1136/ kappa B activation and proinflammatory gene expression by inhibiting inhibitory
gut.2009.199679 (Dec). factor I-kappa B kinase activity. J Immunol. 1999;163(6):3474–3483 (Sep 15).
39. Rashvand S, Somi MH, Rashidkhani B, Hekmatdoost A. Dietary fatty acid intakes are 45. Hanai H, Sugimoto K. Curcumin has bright prospects for the treatment of
related to the risk of ulcerative colitis: a case-control study. Int J Colorectal Dis. 2015; inflammatory bowel disease. Curr Pharm Des. 2009;15(18):2087–2094. https://doi.
30(9):1255–1260. https://doi.org/10.1007/s00384-015-2232-8 (Sep). org/10.2174/138161209788489177.
40. Milajerdi A, Ebrahimi-Daryani N, Dieleman LA, Larijani B, Esmaillzadeh A. 46. Zhang X, Wu J, Ye B, Wang Q, Xie X, Shen H. Protective effect of curcumin on TNBS-
Association of dietary fiber, fruit, and vegetable consumption with risk of induced intestinal inflammation is mediated through the JAK/STAT pathway. BMC
inflammatory bowel disease: a systematic review and meta-analysis. Adv Nutr. 2021; Complement Alter Med. 2016;16(1):299. https://doi.org/10.1186/s12906-016-1273-
12(3):735–743. z (Aug 20).
41. Milajerdi A, Abbasi F, Esmaillzadeh A. A systematic review and meta-analysis of 47. van Ede K, Li A, Antunes-Fernandes E, Mulder P, Peijnenburg A, Hoogenboom R.
prospective studies on obesity and risk of inflammatory bowel disease. Nutr Rev. Bioassay directed identification of natural aryl hydrocarbon-receptor agonists in
2021. marmalade. Anal Chim Acta. 2008;617(1–2):238–245. https://doi.org/10.1016/j.
42. Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and aca.2008.01.054 (Jun 9).
Crohn’s disease. Gastroenterol Clin North Am. 1995;24(3):475–507 (Sep). 48. Veldhoen M, Hirota K, Westendorf AM, et al. The aryl hydrocarbon receptor links
43. Milajerdi A, Sadeghi O, Siadat SD, et al. A randomized controlled trial investigating TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453
the effect of a diet low in fermentable oligosaccharides, disaccharides, (7191):106–109. https://doi.org/10.1038/nature06881 (May 1).
monosaccharides, and polyols on the intestinal microbiome and inflammation in

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