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The efficacy of vitamin D supplementation for irritable bowel syndrome: a systematic review with meta-analysis

Abstract

Background

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder involving gut-brain interactions with limited effective treatment options. Vitamin D deficiency is commonly observed in patients with IBS, but whether vitamin D supplementation ameliorates IBS is controversial in randomized controlled trials. The present systematic review and meta-analysis explored the efficacy of vitamin D supplementation in patients with IBS.

Methods

We performed a systematic search of potentially relevant publications from PubMed, EMBASE, the Cochrane Central Register of Controlled Studies and the Web of Science up until January 2022. We assessed the weighted mean difference (WMD) and 95% confidence interval (95% CI) of the IBS severity scoring system (IBS-SSS), IBS quality of life (IBS-QoL) and IBS total score (IBS-TS) before and after vitamin D supplementation intervention.

Results

We included four randomized, placebo-controlled trials involving 335 participants. The differences in IBS-SSS score between participants in the intervention group and the placebo group increased after intervention (WMD: -55.55, 95% CI: -70.22 to -40.87, I2 = 53.7%, after intervention; WMD: -3.17, 95% CI: -18.15 to 11.81, I2 = 0.0%, before intervention). Participants receiving vitamin D supplementation showed greater improvement in IBS-SSS after intervention than participants receiving placebo treatment (WMD: -84.21, 95% CI: -111.38 to -57.05, I2 = 73.2%; WMD: -28.29, 95% CI: -49.95 to -6.62, I2 = 46.6%, respectively). Vitamin D supplementation was also superior to placebo in IBS-QoL improvement (WMD: 14.98, 95% CI: 12.06 to 17.90, I2 = 0.0%; WMD: 6.55, 95% CI: -2.23 to 15.33, I2 = 82.7%, respectively). Sensitivity analyses revealed an unstable pooled effect on IBS-TS in participants receiving vitamin D supplementation. Therefore, we did not evaluate the efficacy of vitamin D intervention in IBS-TS.

Conclusions

This systematic review and meta-analysis suggested that vitamin D supplementation was superior to placebo for IBS treatment.

Peer Review reports

Introduction

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder involving gut-brain interactions that features recurrent abdominal pain and a changed frequency or form of stool [1]. According to the Rome III criteria, the global prevalence of IBS is 9.2%, and regional prevalence ranges from 0.4 to 29.2% [2]. When the Rome IV criteria, a more restrictive version revised in 2016 [3], was adopted, the global prevalence of IBS was 3.8% [2]. IBS exerts a negative influence on work productivity and quality of life [1]. Patients suffering from IBS may take more time off work and struggle to perform well at work [4], and the extent of work impairment is related to the severity of symptoms [5]. Numerous first-line and second-line therapies for IBS have been established [6]. The bulk of current therapies focus on the most predominant symptoms [7]. However, a personalized and precise treatment for IBS should focus on the underlying pathophysiology rather than predominant symptoms [8]. Novel approaches with limited adverse effects targeting the underlying mechanisms of IBS are needed.

Vitamin D is a fat-soluble vitamin with hormone-like properties that regulates calcium and phosphate homeostasis [9]. Vitamin D deficiency is gradually becoming a global health burden, with a prevalence of 28.9% in the United States [10] and 34.2% in Africa [11]. Several observational studies reported that patients with IBS had a higher prevalence of vitamin D deficiency than controls [12], and vitamin D status was inversely related to IBS [13]. Interventional studies demonstrated that vitamin D supplementation improved depression and anxiety [14, 15], which are common psychological comorbidities in patients with IBS [1]. In addition to the traditional role of vitamin D in skeletal diseases, mounting studies have provided new insights into its anti-inflammatory effect [16]. Low-grade intestinal epithelial inflammation also plays a role in the pathogenesis of IBS [17].

New effective treatments for IBS are needed, and vitamin D may target different aspects of IBS pathophysiology. Therefore, we performed a meta-analysis and systematic review to examine whether vitamin D supplementation effectively improved the symptoms and the quality of life in patients with IBS.

Method

Search strategy

We performed a systematic search of potentially relevant publications from PubMed, EMBASE, the Cochrane Central Register of Controlled Studies and the Web of Science until January 2022. We also searched ClinicalTrials.gov for eligible articles and unpublished trials. No language or age restrictions were imposed. We combined subject and free-text terms of IBS with vitamin D and randomized controlled trials using the set operator AND as our search strategy. To identify more eligible articles, we scanned the references of the reviewed articles. Double-blinded, placebo-controlled, randomized studies evaluating the effectiveness of vitamin D supplementation in the treatment of IBS were included. Vitamin D dose and treatment duration were not pre-specified. We excluded duplicated studies and studies with irrelevant subjects. The complete search strategy is listed in Supplementary Table S1.

Data extraction

Two investigators separately extracted the data needed, including author, publication year, country, study design, number of patients in each group, diagnostic criteria of IBS, IBS subtypes, vitamin D dose, treatment duration and primary and secondary outcomes. The primary outcome was measured using the IBS-severity scoring system (IBS-SSS), which contains 5 items that are scored from 0 to 100 [18]. Higher scores represent more severe symptoms. A decline greater than 50 is considered a significant improvement [18]. The secondary outcome was measured using IBS-quality of life (IBS-QoL) and IBS-total score (IBS-TS), which range from 0 to 100 [19]. In contrast to IBS-SSS scores, lower scores of IBS-QoL and IBS-TS represent poorer outcomes. An increase of 10 points or more in IBS-QoL was viewed as a significant improvement [20]. All data were extracted using intention-to-treat analyses, and discrepancies were resolved by discussion.

Assessment of risk of bias

The risk of bias in each included study was assessed using the Cochrane Collaboration’s tool [21], which considered the following factors: adequate randomization of sequence generation, methods used to conceal allocation, blinding of all measures to participants, eligibility of researchers and outcome assessors, completeness of each outcome, and absence of selective reporting.

Assessment of quality of evidence

Two investigators separately assessed the quality of evidence of IBS-SSS, IBS-QoL and IBS-TS using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) [22].

Statistical analysis

We analyzed the weighted mean difference (WMD) of IBS-SSS, IBS-QoL and IBS-TS before and after vitamin D supplementation or placebo treatment. Chi-squared and I2 statistics were used to assess heterogeneity, and I2 < 25% and P > 0.01 were considered insignificant heterogeneity. Data of studies with significant heterogeneity were analyzed using the random-effect model as described by DerSimonian and Laird. The influence of each study on the pooled effect was measured using sensitivity analyses. Publication bias was quantified using Begg’s test and Egger’s test. Two investigators performed all analyses using STATA 15 (Stata Corporation, College Station, TX) separately.

Result

Search results

We initially identified 149 publications, of which 51 duplicates and 88 records with irrelevant subjects or an inapplicable study type were excluded. Of the 10 remaining articles, 6 studies were excluded after full-text review due to incomplete outcomes or unrelated measurements. Four studies were ultimately included in this meta-analysis (Fig. 1).

Fig. 1
figure 1

Flow diagram of study selection in this systematic review and meta-analysis

Overall, 169 participants receiving vitamin D supplementation and 166 receiving placebos were included using intention-to-treat analyses. As shown in Table 1, three trials, but one diagnosed IBS using the Rome III criteria, because these three trials started before 2016 when the Rome III criteria were revised to a Rome IV [3]. Three studies included all subtypes of IBS, and one study included only IBS-diarrhea. The combination of vitamin D dose and treatment duration varied across studies. A dose of 50,000 IU of vitamin D was provided for the experimental groups fortnightly in two trials, which differed in treatment duration, of 6 weeks or 6 months. A vitamin D dose of 50,000 IU or 2000 IU was provided weekly or daily, respectively, in the other two trials, and the duration of therapy was 9 weeks or 6 months, respectively. There was no report on any adverse effect of vitamin D supplementation in the included trials.

Table 1 Characteristics of randomized controlled trials of vitamin D supplementation on IBS

The risks of bias of the included studies are summarized in Table 2. The risks of random sequence generation and blinding to the outcome assessment in Jalili et al. [26] were not clear. The other risks considered in these studies were all low. Table 3 showed that the GRADE quality of IBS-SSS and IBS-TS were very low and the quality of IBS-QoL was low.

Table 2 Risk of bias of studies included in this meta-analysis
table 3 GRADE quality of evidence of vitamin D versus placebo on IBS

Differences in IBS-SSS, IBS-QoL and IBS-TS before and after intervention

The differences in IBS-SSS scores between participants in the intervention group and the placebo group were greater after intervention than before intervention (WMD: -55.55, 95% CI: -70.22 to -40.87, I2 = 53.7%; WMD: -3.17, 95% CI: -18.15 to 11.81, I2 = 0.0%, respectively) (Fig. 2). Participants receiving vitamin D supplementation showed greater improvement of IBS-SSS than controls (WMD: -84.21, 95% CI: -111.38 to -57.05, I2 = 73.2%; WMD: -28.29, 95% CI: -49.95 to -6.62, I2 = 46.6%, respectively) (Fig. 3). Vitamin D supplementation was superior to placebo in improving IBS-QoL (WMD: 14.98, 95% CI: 12.06 to 17.90, I2 = 0.0%; WMD: 6.55, 95% CI: -2.23 to 15.33, I2 = 82.7%, respectively) (Fig. 4). These results suggested that vitamin D supplementation contributed to a significant improvement in the symptoms and the quality of life in patients with IBS.

Fig. 2
figure 2

Forest plot of the differences in IBS-SSS scores between participants in the intervention group and placebo group before and after intervention. a The differences in IBS-SSS scores between participants in the intervention group and placebo group before intervention; b the differences in IBS-SSS scores between participants in the intervention group and placebo group after intervention

Fig. 3
figure 3

Forest plot of the improvement of IBS-SSS after intervention in participants receiving vitamin D supplementation and receiving placebo. a The improvement of IBS-SSS in participants receiving vitamin D supplementation; b the improvement of IBS-SSS in participants receiving placebo

Fig. 4
figure 4

Forest plot of the improvement of IBS-QoL after intervention in participants receiving vitamin D supplementation and receiving placebo. a The improvement of IBS-QoL in participants receiving vitamin D supplementation; b the improvement of IBS-QoL in participants receiving placebo

Sensitivity analyses and assessment of publication bias

Sensitivity analyses for each of the aforementioned studies showed that the pooled effect remained stable when we omitted each of the studies (Supplementary Figures S1 to S6). However, when we performed sensitivity analyses on the improvement in IBS-TS in participants receiving vitamin D supplementation, the pooled effect was unstable. Therefore, we excluded IBS-TS from our evaluation tools.

We were unable to assess the publication bias due to the limited number of studies included, according to the Cochrane handbook [27].

Discussion

The present systematic review and meta-analysis assessed the efficacy of vitamin D supplementation in improving IBS. We included 4 randomized controlled trials involving 335 participants and found that vitamin D supplementation contributed to improvement of symptoms and quality of life in patients with IBS.

Numerous first-line and second-line therapies for IBS have been established, and emerging treatments were efficacious in randomized controlled trials [6]. Most of these therapies focused on the most predominant symptoms [7]. For example, the first-line therapy for IBS patients with predominant constipation is laxatives and soluble fibers, and the second-line therapy is intestinal secretagogues and 5-hydroxytryptamine4 agonists. Emerging treatments include elobixibat, mizagliflozin and DRAinh-A250 [28]. Abundant treatments for IBS from different aspects, including dietary modification [7], pharmacological [29] and psychological therapies [30], were reported, but how many patients benefit from these treatments and whether the accompanying adverse effects are tolerable remain controversial [28]. Ford et al. [28] summarized that most randomized controlled trials that assessed the efficacies of these treatments had evident methodological limitations, including high risks of research bias, limited coverage of populations, heterogeneity between studies and possible publication bias. For example, the 5-hydroxytryptamine3 antagonist alosetron, which targets IBS with predominant diarrhea, was used restrictively due to its side effects of severe constipation and ischemic colitis [31]. A safer 5-hydroxytryptamine3 antagonist, ramosetron, caused constipation more often than placebo [28]. A personalized and precise treatment for IBS should focus on the underlying pathophysiology rather than predominant symptoms [8]. Therefore, other approaches with limited adverse effects targeting the underlying mechanisms are needed.

We found that vitamin D supplementation showed protective effects on the symptoms and quality of life in patients with IBS in this systematic review and meta-analysis. Vitamin D supplementation may be a promising therapy for the treatment of IBS. Our findings provide significant implications for clinical practice and research. Vitamin D supplementation may be a promising therapy for IBS and target different aspects of IBS pathophysiology. Many first-line therapies targeting the most predominant symptoms of IBS, such as loperamide for diarrhea [32, 33], soluble fibers for constipation [33, 34] and antispasmodic drugs for abdominal pain [35], have beneficial effects on certain symptoms of IBS but contribute little to other symptoms. The symptoms of IBS may shift over time [36, 37]. Therefore, the development of a more individualized and precise treatment strategy for IBS should focus on the underlying pathophysiology of IBS rather than its predominant symptoms [8]. Vitamin D supplementation may meet this goal. Our analyses have fewer methodological limitations than the previous analyses. The Rome criteria for IBS diagnosis was revised from I to IV over the past two decades [38]., and the randomized controlled trials on IBS performed during this time used different versions of the Rome criteria [39, 40]. For example, most randomized controlled trials on alosetron and early trials on ramosetron used Rome I or II [39], but later trials on ramosetron used Rome III [40]. The heterogeneity of participant selection in these trials cannot be ignored, and their pooled effects should be taken more seriously [29].

Notably, most of the participants included in this study were vitamin D deficient or insufficient. The participants enrolled in Jalili et al. [26] and Khalighi et al. [24] had serum vitamin D levels lower than 30 ng/mL, and El Amrousy et al. [25] enrolled participants with serum vitamin D levels lower than 20 ng/mL. In the study conducted by Abbasnezhad et al. [23], the proportions of participants who had serum vitamin D < 20 and < 30 ng/mL were 65.9% and 84.1%, respectively. Abbasnezhad et al. [23] showed that the effects of vitamin D on improving IBS-SSS and IBS-QoL were more significant in participants with vitamin D insufficiency than in participants without insufficiency. Patients with vitamin D insufficiency showed greater improvement in glycemic control after vitamin D supplementation than patients without insufficiency [41, 42]. Further studies are needed to explore the dose and duration of vitamin D therapy that are suitable for different ages, races, sexes and vitamin D statuses.

Notably, participants receiving placebo treatment showed improved IBS-SSS compared with baseline, which indicates placebo effects. Placebo effects may corrupt the efficacy of novel therapies [43]. Previous meta-analyses reported that placebo response rates were 20 − 40% in clinical trials in patients with IBS [44]. Studies with longer trial durations, shorter run-in periods and performed earlier were associated with an increased placebo response rate [45]. Although we observed placebo effects in this meta-analysis, the improvement in IBS-SSS was more significant in participants receiving vitamin D supplementation than the controls.

The precise mechanism of the effectiveness of supplementary vitamin D in improving IBS requires further elucidation. One possible explanation is that vitamin D ameliorates inflammation and the psychological-psychiatric state. Several studies demonstrated that chronic low-grade intestinal mucosal inflammation was a crucial part of the pathogenesis of IBS [17]. Increased release of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukins-6 and − 1β, was found in peripheral mononuclear cells [46] and close to enteric nerve fibers in the intestinal mucosa of patients with IBS [47, 48]. Researchers also observed activated humoral immune responses in peripheral circulation [49] and jejunal mucosa [50] in patients with IBS, characterized by increased proliferation and activation of B lymphocytes [50]. The aforementioned elevated concentrations of cytokines and activated humoral immune responses were positively associated with the severity and frequency of abdominal pain, changed bowel habits [50], and even depression and anxiety [46, 51]. The integrity of the intestinal epithelial barrier is impaired in patients with IBS, presented as changes in tight junction proteins [52]. However, experimental studies found that vitamin D contributed to maintaining the integrity of the intestinal epithelial barrier by inhibiting apoptosis of epithelial cells [53] and regulating tight junction proteins [54]. Vitamin D also exhibited anti-inflammatory effects by suppressing T helper 1 and T helper 17 cells [55, 56] and downregulating the interleukin-23 receptor pathway in innate lymphoid cells [57].

Psychological conditions, such as anxiety and depression, often coexist with IBS [58]. Notably, psychological conditions may be a consequence or predecessor of IBS [59]. For example, patients with more severe anxiety but without IBS at baseline were more likely to develop IBS after a 1-year [60] and 12-year follow-up [61]. Patients with IBS but without psychological comorbidities at baseline had a higher risk of developing anxiety and depression [60, 61]. Therefore, bidirectional communication exists between the central and enteric nervous systems, named gut-brain interactions [61]. The central nervous system influences visceral sensitivity and bowel motility, which are closely related to the typical symptoms of IBS, such as abdominal pain and changed bowel habits. The central nervous system also receives feedback from the bowel and affects psychological conditions [61]. A low level of serum vitamin D is a significant predictor of depression [62], and supplementary vitamin D ameliorates symptoms of anxiety and depression [14, 15], by reducing the elevated concentration of Ca2+ in inhibitory neurons [63]. Overall, vitamin D may exert beneficial effects on IBS via multiple mechanisms that are crucial to the pathogenesis of IBS.

There are several limitations in the present systematic review and meta-analysis. First, only four studies were included. Due to this limited number, publication bias was not evaluated. Second, three of the four included studies were from Iran, and the other was from Egypt. We also found several relevant studies performed in other countries, which were regretfully terminated due to low enrollment. For example, one trial in the United States was terminated because only 7 participants were ultimately enrolled. The effectiveness of supplementary vitamin D in treating IBS must be further elucidated in other populations. Third, the risk of adequate random sequence generation and information on blinding in the study design were unclear in Jalili et al. [26].

Conclusions

In summary, our results suggest that vitamin D supplementation effectively improves the symptoms and the quality of life in patients with IBS. Vitamin D is inexpensive and safe and may be a useful and practical approach for IBS treatment.

Availability of data and material

The data of the present study will be available for the corresponding author.

References

  1. Black CJ, Ford AC. Global burden of irritable bowel syndrome: trends, predictions and risk factors. Nat Rev Gastroenterol Hepatol. 2020;17:473–86. doi:https://doi.org/10.1038/s41575-020-0286-8.

    Article  PubMed  Google Scholar 

  2. Oka P, Parr H, Barberio B, Black CJ, Savarino EV, Ford AC. Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5:908–17. doi:https://doi.org/10.1016/S2468-1253(20)30217-X.

    Article  PubMed  Google Scholar 

  3. Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel Disorders Gastroenterology. 2016;150:1393–407. doi:https://doi.org/10.1053/j.gastro.2016.02.031.

    Article  Google Scholar 

  4. Akehurst RL, Brazier JE, Mathers N, O’Keefe C, Kaltenthaler E, Morgan A, et al. Health-related quality of life and cost impact of irritable bowel syndrome in a UK primary care setting. PharmacoEconomics. 2002;20:455–62. doi:https://doi.org/10.2165/00019053-200220070-00003.

    Article  PubMed  Google Scholar 

  5. Frändemark Å, Törnblom H, Jakobsson S, Simrén M. Work Productivity and Activity Impairment in Irritable Bowel Syndrome (IBS): A Multifaceted Problem. Am J Gastroenterol. 2018;113:1540–9. doi:https://doi.org/10.1038/s41395-018-0262-x.

    CAS  Article  PubMed  Google Scholar 

  6. Simrén M, Tack J. New treatments and therapeutic targets for IBS and other functional bowel disorders. Nat Rev Gastroenterol Hepatol. 2018;15:589–605. doi:https://doi.org/10.1038/s41575-018-0034-5.

    CAS  Article  PubMed  Google Scholar 

  7. Camilleri M. Management Options for Irritable Bowel Syndrome. Mayo Clin Proc. 2018;93:1858–1872. doi: https://doi.org/10.1016/j.mayocp.2018.04.032.

  8. Camilleri M, Shin A, Busciglio I, Carlson P, Acosta A, Bharucha AE, et al. Validating biomarkers of treatable mechanisms in irritable bowel syndrome. Neurogastroenterol Motil. 2014;26:1677–85. doi:https://doi.org/10.1111/nmo.12421.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40:1109–51. doi:https://doi.org/10.1210/er.2018-00126.

    Article  PubMed  Google Scholar 

  10. Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications. Br J Nutr. 2018;119:928–36. doi:https://doi.org/10.1017/S0007114518000491.

    CAS  Article  PubMed  Google Scholar 

  11. Mogire RM, Mutua A, Kimita W, Kamau A, Bejon P, Pettifor JM, et al. Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis. Lancet Glob Health. 2020;8:e134–42. doi:https://doi.org/10.1016/S2214-109X(19)30457-7.

    Article  PubMed  Google Scholar 

  12. Nwosu BU, Maranda L, Candela N. Vitamin D status in pediatric irritable bowel syndrome. PLoS ONE. 2017;12:e0172183. doi:https://doi.org/10.1371/journal.pone.0172183.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Barbalho SM, Goulart RA, Araújo AC, Guiguer ÉL, Bechara MD. Irritable bowel syndrome: a review of the general aspects and the potential role of vitamin D. Expert Rev Gastroenterol Hepatol. 2019;13:345–59. doi:https://doi.org/10.1080/17474124.2019.1570137.

    CAS  Article  PubMed  Google Scholar 

  14. Casseb GAS, Kaster MP, Rodrigues ALS. Potential Role of Vitamin D for the Management of Depression and Anxiety. CNS Drugs. 2019;33:619–37. doi:https://doi.org/10.1007/s40263-019-00640-4.

    CAS  Article  PubMed  Google Scholar 

  15. Jamilian H, Amirani E, Milajerdi A, Kolahdooz F, Mirzaei H, Zaroudi M, et al. The effects of vitamin D supplementation on mental health, and biomarkers of inflammation and oxidative stress in patients with psychiatric disorders: A systematic review and meta-analysis of randomized controlled trials. Prog Neuropsychopharmacol Biol Psychiatry. 2019;94:109651. doi:https://doi.org/10.1016/j.pnpbp.2019.109651.

    CAS  Article  PubMed  Google Scholar 

  16. Filgueiras MS, Rocha NP, Novaes JF, Bressan J. Vitamin D status, oxidative stress, and inflammation in children and adolescents: A systematic review. Crit Rev Food Sci Nutr. 2020;60:660–9. doi:https://doi.org/10.1080/10408398.2018.1546671.

    CAS  Article  PubMed  Google Scholar 

  17. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol. 2016;1:133–46. doi:https://doi.org/10.1016/S2468-1253(16)30023-1.

    Article  PubMed  Google Scholar 

  18. Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11:395–402. doi:https://doi.org/10.1046/j.1365-2036.1997.142318000.x.

    CAS  Article  PubMed  Google Scholar 

  19. Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43:400–11. doi:https://doi.org/10.1023/a:1018831127942.

    CAS  Article  PubMed  Google Scholar 

  20. Drossman D, Morris CB, Hu Y, Toner BB, Diamant N, Whitehead WE, et al. Characterization of health related quality of life (HRQOL) for patients with functional bowel disorder (FBD) and its response to treatment. Am J Gastroenterol. 2007;102:1442–53. doi:https://doi.org/10.1111/j.1572-0241.2007.01283.x.

    Article  PubMed  Google Scholar 

  21. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi:https://doi.org/10.1136/bmj.d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–94. doi:https://doi.org/10.1016/j.jclinepi.2010.04.026.

    Article  PubMed  Google Scholar 

  23. Abbasnezhad A, Amani R, Hajiani E, Alavinejad P, Cheraghian B, Ghadiri A. Effect of vitamin D on gastrointestinal symptoms and health-related quality of life in irritable bowel syndrome patients: a randomized double-blind clinical trial. Neurogastroenterol Motil. 2016;28:1533–44. doi:https://doi.org/10.1111/nmo.12851.

    CAS  Article  PubMed  Google Scholar 

  24. Khalighi Sikaroudi M, Mokhtare M, Janani L, Faghihi Kashani AH, Masoodi M, Agah S, et al. Vitamin D3 Supplementation in Diarrhea-Predominant Irritable Bowel Syndrome Patients: The Effects on Symptoms Improvement, Serum Corticotropin-Releasing Hormone, and Interleukin-6 - A Randomized Clinical Trial. Complement Med Res. 2020;27:302–9. doi:https://doi.org/10.1159/000506149.

    Article  PubMed  Google Scholar 

  25. El Amrousy D, Hassan S, El Ashry H, Yousef M, Hodeib H. Vitamin D supplementation in adolescents with irritable bowel syndrome: Is it useful? A randomized controlled trial. Saudi J Gastroenterol. 2018;24:109–14. doi:https://doi.org/10.4103/sjg.SJG_438_17.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jalili M, Hekmatdoost A, Vahedi H, Poustchi H, Khademi B, Saadi M, et al. Co-Administration of soy isoflavones and Vitamin D in management of irritable bowel disease. PLoS ONE. 2016;11:e0158545. doi:https://doi.org/10.1371/journal.pone.0158545.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.

  28. Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet. 2020;396:1675–88. doi:https://doi.org/10.1016/S0140-6736(20)31548-8.

    CAS  Article  PubMed  Google Scholar 

  29. Black CJ, Burr NE, Camilleri M, Earnest DL, Quigley EM, Moayyedi P, et al. Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis. Gut. 2020;69:74–82. doi:https://doi.org/10.1136/gutjnl-2018-318160.

    CAS  Article  PubMed  Google Scholar 

  30. Black CJ, Thakur ER, Houghton LA, Quigley EMM, Moayyedi P, Ford AC. Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2020;69:1441–51. doi:https://doi.org/10.1136/gutjnl-2020-321191.

    Article  PubMed  Google Scholar 

  31. Tennis P, Andrews E, Hickman P, Miller D, Hollis K, Cook S. The relationship between dosing of alosetron and discontinuation patterns reported by patients participating in a follow-up programme. Aliment Pharmacol Ther. 2007;25:317–22. doi:https://doi.org/10.1111/j.1365-2036.2006.03198.x.

    CAS  Article  PubMed  Google Scholar 

  32. Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig Dis Sci. 1984;29:239–47. doi:https://doi.org/10.1007/BF01296258.

    CAS  Article  PubMed  Google Scholar 

  33. Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109 Suppl 1. doi:https://doi.org/10.1038/ajg.2014.187.

  34. Bijkerk CJ, de Wit NJ, Muris JWM, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ. 2009;339:b3154. doi:https://doi.org/10.1136/bmj.b3154.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Ford AC, Talley NJ, Spiegel BMR, Foxx-Orenstein AE, Schiller L, Quigley EMM, et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008;337:a2313. doi:https://doi.org/10.1136/bmj.a2313.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Engsbro AL, Simren M, Bytzer P. Short-term stability of subtypes in the irritable bowel syndrome: prospective evaluation using the Rome III classification. Aliment Pharmacol Ther. 2012;35:350–9. doi:https://doi.org/10.1111/j.1365-2036.2011.04948.x.

    CAS  Article  PubMed  Google Scholar 

  37. Drossman DA, Morris CB, Hu Y, Toner BB, Diamant N, Leserman J, et al. A prospective assessment of bowel habit in irritable bowel syndrome in women: defining an alternator. Gastroenterology. 2005;128:580–9. doi:https://doi.org/10.1053/j.gastro.2004.12.006.

    Article  PubMed  Google Scholar 

  38. Lacy BE, Patel NK. Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome. J Clin Med. 2017;6:99. doi:https://doi.org/10.3390/jcm6110099.

    Article  PubMed Central  Google Scholar 

  39. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Müller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut. 1999;45 Suppl 2:II43-II47. doi: https://doi.org/10.1136/gut.45.2008.ii43.

  40. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–91. doi:https://doi.org/10.1053/j.gastro.2005.11.061.

    Article  PubMed  Google Scholar 

  41. Wu C, Qiu S, Zhu X, Li L. Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systematic review and meta-analysis. Metabolism. 2017;73:67–76. doi:https://doi.org/10.1016/j.metabol.2017.05.006.

    CAS  Article  PubMed  Google Scholar 

  42. Krul-Poel YHM, Westra S, ten Boekel E, ter Wee MM, van Schoor NM, van Wijland H, et al. Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial. Diabetes Care. 2015;38:1420–1426. doi: https://doi.org/10.2337/dc15-0323.

  43. Enck P, Klosterhalfen S. Placebo Responses and Placebo Effects in Functional Gastrointestinal Disorders. Front Psychiatry. 2020;11:797. doi:https://doi.org/10.3389/fpsyt.2020.00797.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Elsenbruch S, Enck P. Placebo effects and their determinants in gastrointestinal disorders. Nat Rev Gastroenterol Hepatol. 2015;12:472–85. doi:https://doi.org/10.1038/nrgastro.2015.117.

    Article  PubMed  Google Scholar 

  45. Bosman M, Elsenbruch S, Corsetti M, Tack J, Simrén M, Winkens B, et al. The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6:459–73. doi:https://doi.org/10.1016/S2468-1253(21)00023-6.

    Article  PubMed  Google Scholar 

  46. Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, et al. Immune activation in patients with irritable bowel syndrome. Gastroenterology. 2007;132:913–20. doi:https://doi.org/10.1053/j.gastro.2007.01.046.

    CAS  Article  PubMed  Google Scholar 

  47. Mearin F, Perelló A, Balboa A, Perona M, Sans M, Salas A, et al. Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis. Scand J Gastroenterol. 2009;44:1173–85. doi:https://doi.org/10.1080/00365520903171276.

    CAS  Article  PubMed  Google Scholar 

  48. Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52:523–6. doi:https://doi.org/10.1136/gut.52.4.523.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Ohman L, Lindmark AC, Isaksson S, Posserud I, Strid H, Sjövall H, et al. B-cell activation in patients with irritable bowel syndrome (IBS). Neurogastroenterol Motil. 2009;21:644 – 50,e27. doi: https://doi.org/10.1111/j.1365-2982.2009.01272.x.

  50. Vicario M, González-Castro AM, Martínez C, Lobo B, Pigrau M, Guilarte M, et al. Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations. Gut. 2015;64:1379–88. doi:https://doi.org/10.1136/gutjnl-2013-306236.

    CAS  Article  PubMed  Google Scholar 

  51. Zhen Y, Chu C, Zhou S, Qi M, Shu R. Imbalance of tumor necrosis factor-α, interleukin-8 and interleukin-10 production evokes barrier dysfunction, severe abdominal symptoms and psychological disorders in patients with irritable bowel syndrome-associated diarrhea. Mol Med Rep. 2015;12:5239–45. doi:https://doi.org/10.3892/mmr.2015.4079.

    CAS  Article  PubMed  Google Scholar 

  52. Bertiaux-Vandaële N, Youmba SB, Belmonte L, Lecleire S, Antonietti M, Gourcerol G, et al. The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype. Am J Gastroenterol. 2011;106:2165–73. doi:https://doi.org/10.1038/ajg.2011.257.

    CAS  Article  PubMed  Google Scholar 

  53. He L, Liu T, Shi Y, Tian F, Hu H, Deb DK, et al. Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell Apoptosis. Endocrinology. 2018;159:967–79. doi:https://doi.org/10.1210/en.2017-00748.

    CAS  Article  PubMed  Google Scholar 

  54. Du J, Chen Y, Shi Y, Liu T, Cao Y, Tang Y, et al. 1,25-Dihydroxyvitamin D Protects Intestinal Epithelial Barrier by Regulating the Myosin Light Chain Kinase Signaling Pathway. Inflamm Bowel Dis. 2015;21:2495–506. doi:https://doi.org/10.1097/MIB.0000000000000526.

    Article  PubMed  Google Scholar 

  55. Cantorna MT, Snyder L, Lin Y-D, Yang L. Vitamin D. and 1,25(OH)2D regulation of T cells. Nutrients. 2015;7:3011–21. doi:https://doi.org/10.3390/nu7043011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Zhang H, Wu H, Liu L, Li H, Shih DQ, Zhang X. 1,25-dihydroxyvitamin D3 regulates the development of chronic colitis by modulating both T helper (Th)1 and Th17 activation. APMIS. 2015;123:490–501. doi:https://doi.org/10.1111/apm.12378.

    CAS  Article  PubMed  Google Scholar 

  57. Konya V, Czarnewski P, Forkel M, Rao A, Kokkinou E, Villablanca EJ, et al. Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells. J Allergy Clin Immunol. 2018;141:279–92. doi:https://doi.org/10.1016/j.jaci.2017.01.045.

    CAS  Article  PubMed  Google Scholar 

  58. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122:1140–56. doi:https://doi.org/10.1053/gast.2002.32392.

    Article  PubMed  Google Scholar 

  59. Van Oudenhove L, Crowell MD, Drossman DA, Halpert AD, Keefer L, Lackner JM, et al. Biopsychosocial Aspects of Functional Gastrointestinal Disorders. Gastroenterology. 2016;S0016-5085:00218–3. doi:https://doi.org/10.1053/j.gastro.2016.02.027.

    Article  Google Scholar 

  60. Koloski NA, Jones M, Talley NJ. Evidence that independent gut-to-brain and brain-to-gut pathways operate in the irritable bowel syndrome and functional dyspepsia: a 1-year population-based prospective study. Aliment Pharmacol Ther. 2016;44:592–600. doi:https://doi.org/10.1111/apt.13738.

    CAS  Article  PubMed  Google Scholar 

  61. Koloski NA, Jones M, Kalantar J, Weltman M, Zaguirre J, Talley NJ. The brain–gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut. 2012;61:1284–90. doi:https://doi.org/10.1136/gutjnl-2011-300474.

    CAS  Article  PubMed  Google Scholar 

  62. Anglin RES, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100–7. doi:https://doi.org/10.1192/bjp.bp.111.106666.

    Article  PubMed  Google Scholar 

  63. Berridge MJ. Vitamin D and Depression: Cellular and Regulatory Mechanisms. Pharmacol Rev. 2017;69:80–92. doi:https://doi.org/10.1124/pr.116.013227.

    CAS  Article  PubMed  Google Scholar 

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This work was supported by National Key Research and Development Program of China (2018YFA0109800).

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Hangkai Huang conceived the study, analyzed the data and wrote the manuscript. Linjie Lu, Yishu Chen and Yan Zeng analyzed the data. Chengfu Xu was responsible for the study design and revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chengfu Xu.

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Huang, H., Lu, L., Chen, Y. et al. The efficacy of vitamin D supplementation for irritable bowel syndrome: a systematic review with meta-analysis. Nutr J 21, 24 (2022). https://doi.org/10.1186/s12937-022-00777-x

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Keywords

  • Irritable bowel syndrome
  • Vitamin D
  • meta-analysis