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Research Article: Study Protocol Systematic Review

Probiotics, prebiotics, antibiotic, Chinese herbal medicine, and fecal microbiota transplantation in irritable bowel syndrome

Protocol for a systematic review and network meta-analysis

He, Ying MDa; Xu, Rui MSa; Wang, Wei MSb; Zhang, Jie MDa; Hu, Xiaoyu MDa,∗

Author Information
doi: 10.1097/MD.0000000000021502
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1 Introduction

Irritable bowel syndrome (IBS) is a type of functional gastrointestinal disorders (FGIDs), characterized by recurrent abdominal pain, which is associated with defecation or accompanied by changes in bowel habits.[1] IBS is a frequent FGIDs with a global prevalence of approximately 10%, and the prevalence is lowest in Southeast Asia (7%), while in South America, the incidence is about 3 times that of South Asia (21%).[2] In Europe, the prevalence of IBS with constipation (IBS-C) or IBS with a mixed bowel pattern (IBC-M) may be higher than IBS with diarrhea (IBS-D).[3] The symptoms of patients vary with each subtype, but there is no doubt that IBS will seriously affect patients’ quality of life and work efficiency, and increase social medical expenditure.[4] The etiology and pathogenesis of IBS remain unknown. Treatment strategies target symptoms only cannot help the patients to recover and back to normal life.[5] According to the recommendations of Rome IV treatments of IBS mainly include peripheral drugs, systemic drugs, microbial/immunomodulatory therapy, and complementary and alternative medicine (CAM). Accumulating evidence suggests that IBS is closely related to the change of intestinal microorganisms. Studies have shown a negative correlation between abdominal pain and the abundance of Bifidobacteria in the intestinal cavity.[6] Based on this, treatment strategies targeting the intestinal flora are being actively implemented in IBS. The definition of microbial therapy in Roman IV mainly includes the following categories: probiotics, antibiotics, prebiotics, and special diets. Probiotics are defined as living microorganisms that confer a health benefit to the host, lactic acid bacteria, and Bifidobacteria are the most prevalent used probiotics.[7,8] Up to date, probiotics have been widely used to treat gastrointestinal diseases.[9] Results of a double-blind, randomized placebo-controlled trial suggest that probiotic supplementation can relieve clinical symptoms in patients with IBS.[10] Prebiotics is a nondigestible food ingredient that stimulates the growth of favorable microbial strains in the gut, thereby benefiting the host.[11] The effectiveness of antibiotics in the treatment of IBS has long been confirmed. Rifaximin has played an important role in the treatment of IBS as a non-oral absorption spectrum antibiotic. Rifaximin can reduce the overall symptoms and bloating symptoms of IBS patients and the efficacy is significantly better than the placebo.[12,13] However, the use of antibiotics will induce an imbalance of intestinal bacterial flora, increasing the risk to develop antibiotic-associated diarrhea caused by C. difficile infection.[14,15] Among the recommended treatments for IBS in Roman IV, fecal microbiota transplantation (FMT) is considered a very promising treatment and is successfully used to treat IBS.[16] FMT can achieve the therapeutic effect through the restoration of a healthy microbiota.[17] CAM is of great significance in the treatment of IBS. Almost 30% to 50% of patients with FGIDs have received CAM treatment.[18,19] As the most representative type of CAM therapy, CHM has accumulated rich experience in the treatment of IBS. Studies have shown that CHM can effectively improve IBS symptoms without significantly increasing adverse reactions.[20] There are a variety of chemical ingredients in CHM including rich polysaccharides and glycosides, which are regarded as a natural prebiotic.[21] Studies have shown that as major active components of ginseng, polysaccharide can greatly restore the intestinal flora.[22] Due to the important role of natural medicines in the treatment of IBS and its special regulation function on the intestinal flora, CHM should be included in the analysis of IBS microecological adjustment treatment methods to make the study more comprehensive.

With the in-depth study of intestinal flora, the importance of intestinal flora has been more and more confirmed. All the 5 treatment schemes mentioned above can have an impact on the intestinal flora of patients. However, these 5 treatment methods all have their own advantages and disadvantages, so far there is no direct comparison between them. Therefore, this study will conduct an network meta-analysis (NMA) to indirectly compare the safety and efficacy of these 5 methods in the treatment of IBS, and select the optimal scheme for the treatment of IBS, which will provide scientific evidence for clinicians in the selection of treatment strategies for IBS.

2 Methods

2.1 Protocol register

This study is a systematic review and meta-analysis of interventional studies on IBS. The final results will be reported according to the guidelines of Preferred Reporting Items for network meta-analyses (PRISMA-NMA).[23] The study protocol will be drafted according to the recommendations listed in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P).[24] This protocol has been registered on the INPLASY platform ( with an assigned registration number INPLASY202050047.

2.2 Ethics and dissemination

This is a re-study of the results of existing research. Subjects were not directly included for analysis, so ethical approval is not needed for this study. The findings will be disseminated through conference presentations, media, and peer-reviewed journals.

2.3 Inclusion and exclusion criteria

2.3.1 Types of study

Randomized controlled trials.

2.3.2 Participants

We will include studies in which the diagnostic criteria for IBS patients must meet Manning criteria, Rome I, Rome II, Rome III, Rome IV criteria, or the Kruis score. Subjects are adults aged ≥ 18 years.

2.3.3 Interventions

Treatment strategies include the following 5: Oral CHM treatment under the guidance of syndrome differentiation, and no restrictions on dosage forms, probiotics, prebiotics, antibiotics, fecal transplantation via oral capsule administration. All 5 methods listed above can be used as monotherapy or combined treatments, and the minimum treatment duration is 7 days. Controlled interventions will include a placebo or another intervention in the five treatments mentioned above.

2.3.4 Outcome measures

Primary outcomes will include efficacy assessments of global symptoms cure or improvement from baseline to end of study. The secondary outcomes will include the effect of therapy on individual IBS symptom scores (abdominal pain, distension, and urgency); Emotional response; The number of adverse events and withdrawal due to adverse events. In recent years, various instruments are available for the assessment of IBS symptoms. We will not limit the types of IBS symptoms evaluation criteria in this systematic review. Outcome measurement information is preferably reported by the patient, but if this is unavailable then as assessed by a physician or data obtained through questionnaires are acceptable.[25] Studies that do not meet the inclusion criteria or that are difficult to extract data from will be excluded.

2.4 Literature search strategy

The following electronic databases will be searched: Embase, Pubmed, Cochrane Central Register of Controlled Trials, and Chinese Biomedical Literature Database. We will also search other trial databases, including WHO International Clinical Trials Registry Platform (apps. trialsearch/), and ( to collect studies with results but not yet published and to find other supplementary information of the included trials. The search strategy will include medical subject headings (MeSH) and keywords associated with prebiotics, probiotics, antibiotics, FMT, and CHM in the treatment of IBS. All databases will be searched from inception to June 2020 without language restrictions. Besides, reference lists of all retrieved articles especially related review articles will be also manually examined. The example of search strategy for PubMed is shown in Table 1.

Table 1
Table 1:
Search strategy in PubMed.

2.5 Selection of literatures

We will import all retrieved studies into EndNote (version X9, Thomson, Philadephia, PA/USA) and then remove any duplicates. Two researchers (YH and RX) will first independently scan the title and abstract then the full articles will be read when the abstracts lack the information. The articles will be screened according to the pre-established inclusion and exclusion criteria. Any disagreement will be resolved through discussion or underwent third-party adjudication. The flow diagram of literature screening is shown in Figure 1.

Figure 1
Figure 1:
Flow diagram of the study selection.

2.6 Data extraction and management

Two researchers (YH and RX) will independently extract the data according to the following scheme, and the inconsistencies will be reviewed and corrected.

2.6.1 Literature Basic Information

Authors, location, and publication year.

2.6.2 Subject characteristics

Number and gender distribution of patients in the treatment group and the control group. IBS severity, IBS subtypes, race, sex, age, and IBS diagnostic criteria.

2.6.3 Intervention

Treatment method, control treatment, duration, and follow-up time at post-treatment.

2.6.4 Assessment of risk of bias

We will extract relevant information according to the bias evaluation table listed in Cochrane

2.6.5 Outcome measures

All data related to outcome indicators will be extracted.

2.7 Assessment of risk of bias

The risk of bias for each study included will be assessed independently by 2 researchers (YH and RX) on the basis of the Cochrane risk-of-bias tool.[26] Six items are included and focused: random sequence generation, allocation concealment, blinding (participants, researchers, and assessors of outcomes), incomplete outcome data, selective reporting, and other bias. Any disagreement will be resolved by consensus or underwent third-party adjudication.

2.8 Data analysis

The conventional pair-wise meta-analysis of the direct comparison will be performed using Stata software Stata 14.0 (Stata Corporation, College Station, USA). Data were pooled using a random-effects model because the random effects model will give a more conservative estimate of the precision of the effects in IBS treatment. For dichotomous data, we will use relative risk (RR) with 95% confidence intervals (CI) as the effect measure, and the effect measure of the continuous outcome will be expressed as standardized mean differences (SMD) with 95% CI. Due to the different experimental methods and measuring tools, the existence of heterogeneity between studies is inevitable. Chi-squared test and I2 tests are determined to evaluate the level of heterogeneity between each paired comparison. The significant degree of heterogeneity will be considered where I2 is >50% and the Chi-squared test with a P < .10.[27] If obvious heterogeneity is found between studies, sensitivity, and subgroup analysis will be applied to examine the source of heterogeneity. If quantitative synthesis is not appropriate, describe the type of summary planned.

Various interventions to treat IBS will be drawn into a network diagram to show direct and indirect comparison. Meanwhile, a funnel plot was drawn for qualitative judgment of publication bias. If the graph was roughly symmetrical, it was considered that there was no publication bias. We will use Stata software (StataV.14.0, StataCorp) to accomplish the network diagram and funnel plot. We will use WinBUGS, version 1.4.3 (Cambridge, United Kingdom) with a Bayesian hierarchical random-effects model to conduct the NMA. To check the consistency of the NMA, the node-split method will be used to determine the location of the inconsistency between direct and indirect treatment effects.[28] The P > .05 is considered to be no statistically significant between direct and indirect comparisons, which means the consistency model will be used for NMA analysis; otherwise, the inconsistency model will be conducted.[28] Factors that lead to inconsistency will be discussed later. Finally, we will use the ranking probabilities plots to compare the effects of various interventions.

2.9 GRADE quality assessment

We will use the GRADEprofiler version 3.6.1 (GRADE Working Group) to assess the quality of evidence, the confidence in each network will be divided into 4 levels including high, medium, low, and extremely low.[29]

3 Discussion

Since the importance of intestinal microbes has been widely discussed, more and more attention has been paid to the therapeutic strategies targeting intestinal flora. These 5 therapies (Probiotics, prebiotics, antibiotics, CHM, and FMT) have the commonality of producing therapeutic effects by affecting patients’ intestinal flora, and have been widely used in actual clinical and proved effective. Currently, there has been a study systematically evaluate the effectiveness and safety of probiotics, prebiotics, and antibiotics in the treatment of IBS. However, the content is not comprehensive enough to include fecal bacteria transplantation, a promising new therapy and neither does CHM. Although the mechanism of CHM in IBS has not been determined, it has been widely confirmed that CHM can improve IBS symptoms by regulating the intestinal flora of patients.[30,31] At present, there is a lack of NMA to indirectly compare these 5 treatments. The existing systematic reviews or meta-analysis rarely discuss CHM together with other micro-ecological adjustment drugs, which is obviously 1-sided. Based on this, this study indirectly compared the efficacy and safety of 5 different treatment methods mentioned above for IBS with the method of NMA and selected the optimal scheme. This result can provide clinicians with an evidence-based medical decision-making basis.

Author contributions

Data selection, extraction, and bias analysis: Ying He, Rui Xu, Wang Wei, Xiaoyu Hu. ”

Database retrieval: Ying He, Jie Zhang.

Investigation: Ying He, Jie Zhang.

Methodology: Ying He, Rui Xu, Wei Wang.

Software: Jie Zhang.

Supervision: Xiaoyu Hu.

Writing – original draft: Ying He.

Writing – review & editing: Ying He, Xiaoyu Hu.


[1]. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol 2014;6:71–80.
[2]. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10:712–21.
[3]. Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in irritable bowel syndrome: systematic review. Am J Gastroenterol 2005;100:1174–84.
[4]. Steffen R, Hill DR, DuPont HL. Traveler's diarrhea: a clinical review. JAMA 2015;313:71–80.
[5]. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol 2016;1:133–46.
[6]. Jalanka-Tuovinen J, Salonen A, Nikkilä J, et al. Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms. PLoS One 2011;6:1–3.
[7]. Kopp-Hoolihan L. Prophylactic and therapeutic uses of probiotics: a review. J Am Diet Assoc 2001;101:229–41.
[8]. Didari T, Solki S, Mozaffari S, et al. A systematic review of the safety of probiotics. Expert Opin Drug Saf 2014;13:227–39.
[9]. Shen J, Zuo ZX, Mao AP. Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn's disease, and pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis 2014;20:21–35.
[10]. Kajander K, Myllyluoma E, Rajilić-Stojanović M, et al. Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota. Aliment Pharmacol Ther 2008;27:48–57.
[11]. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401–12.
[12]. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364:22–32.
[13]. Menees SB, Maneerattannaporn M, Kim HM, et al. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol 2012;107:28–36.
[14]. Isakow W, Morrow LE, Kollef MH. Probiotics for preventing and treating nosocomial infections: review of current evidence and recommendations. Chest 2007;132:286–94.
[15]. Martin JS, Monaghan TM, Wilcox MH. Clostridium difficile infection: epidemiology, diagnosis and understanding transmission. Nat Rev Gastroenterol Hepatol 2016;13:206–16.
[16]. Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 2011;9:88–96.
[17]. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent clostridium difficile. N Engl J Med 2013;368:407–15.
[18]. Kong SC, Hurlstone DP, Pocock CY, et al. The Incidence of self-prescribed oral complementary and alternative medicine use by patients with gastrointestinal diseases. J Clin Gastroenterol 2005;39:138–41.
[19]. van Tilburg MA, Palsson OS, Levy RL, et al. Complementary and alternative medicine use and cost in functional bowel disorders: a six month prospective study in a large HMO. BMC Complement Altern Med 2008;8:1–7.
[20]. Shi J, Tong Y, Shen JG, et al. Effectiveness and safety of herbal medicines in the treatment of irritable bowel syndrome: a systematic review. World J Gastroenterol 2008;14:454–62.
[21]. Xu J, Chen HB, Li SL. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota. Med Res Rev 2017;37:1140–85.
[22]. Zhou SS, Xu J, Zhu H, et al. Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysacchar-ides in ginseng decoction. Sci Rep 2016;6:1–3.
[23]. Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extensionstatement for reporting of systematic reviews incorporating networkmeta-analyses of health care interventions: checklist and explanations. Ann Intern Med 2015;11:777–84.
[24]. Moher D, Shamseer L, Clarke M, et al. Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1–9.
[25]. Ford AC, Harris LA, Lacy BE, et al. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther 2018;48:1044–60.
[26]. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:1–9.
[27]. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58.
[28]. Dias S, Welton NJ, Caldwell DM, et al. Checking consistency in mixed treatment comparison meta-analysis. Stat Med 2010;29:932–44.
[29]. Schünemann H, Bro zek J, Guyatt G, et al GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE working group.
[30]. Peng Y, Wang Z, Lu Y, et al. Intestinal microflora molecular markers of spleen-deficient rats and evaluation of traditional Chinese drugs. World J Gastroenterol 2009;15:2220–7.
[31]. Peng Y, Wu C, Yang J, et al. Gut microbial diversity in rat model induced by rhubarb. Exp Anim 2014;63:415–22.

antibiotic; Chinese herbal medicine; fecal microbiota transplantation; network meta-analysis; prebiotics; probiotics; protocol

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.