설사

Irritable bowel syndrome (IBS) affects 7–15% of the general population. A recently devised dietary approach consists of restricting foods with highly fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs), which can trigger and/or exacerbate IBS symptoms. The aim of this study is to use meta-analysis to provide an update on the randomised control trials (RCTs) and cohort studies, and examine them separately in relation to diet type. Papers were selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. Cohen’s d and odds ratios were used as a measure of effect size for RCTs. A random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics, I2, Tau, and Tau2. Publication bias was analysed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger’s test. The results showed that in the RCTs, the patients receiving a low-FODMAP diet experienced a statistically significant pain and bloating reduction compared with those receiving a traditional diet; as regards to stool consistency, there was no significant difference between treatments. A significant reduction in abdominal pain and bloating were described by patients receiving a low-FODMAP diet compared with those receiving a high-FODMAP diet. In cohort studies, pain and bloating were significantly reduced after treatment compared with the baseline diet. We conclude that there is evidence that a low-FODMAP diet could have a favourable impact on IBS symptoms, especially abdominal pain and bloating. However, it remains to be demonstrated whether a low-FODMAP diet is superior to conventional IBS diets, especially in the long term.

The search found 362 records in the databases and eight records through the manual search. After the removal of 132 duplicates there remained 238 papers; of these, 215 were excluded for different reasons (Figure 1). In the second phase of the PRISMA flow-chart, full-text articles were identified for eligibility; of these, 11 were excluded for the following reasons: three compared the FODMAP to a placebo, lactobacillus, or hypnotherapy, one considered healthy controls versus IBD patients; one involved a paediatric population; one administered the FODMAP to non-celiac gluten-sensitive patients; one included interventions that only regarded two different types of rye bread (normal versus low-FODMAP rye bread); one study reviewed two different types of educational training; one was a retrospective study; one regarded fructose restriction; and finally one did not include any outcomes of interest for our study. This left six RCTs, of which three compared the traditional IBS diet to the low-FODMAP diet and three compared the low- and high-FODMAP diets (Table 1). Six cohort studies compared patients’ conditions at baseline and after administration of the low-FODMAP diet (Table 2). In each meta-analysis, sensitivity analysis indicated that the meta-analytical findings were stable.

3.1. Low-FODMAP Diet Versus Traditional IBS Diet: The primary studies (k = 3 RCTs) by Bohn, Eswaran, and Staudacher compared groups of IBS patients receiving a low-FODMAP diet to those receiving a traditional diet. These studies examined four outcomes: reduction of abdominal pain, reduction of abdominal bloating, increase of stool consistency, and reduction of stool frequency. Their main features are reported in Table 1.

3.1.1. Abdominal Pain: The present meta-analysis demonstrates that the patients receiving a low-FODMAP diet experienced a statistically significant pain reduction compared to those receiving a traditional diet. The overall effect size was odds ratio (OR) = 0.44 (Table 3); there was no statistical heterogeneity (Table 3, Figure 2A). Publication bias analysis did not highlight any differences between observed and estimated values (zero trimmed studies) (Figure 2B). Egger’s test was not statistically significant (Table 3).

3.1.2. Bloating: Patients managed with a low-FODMAP diet experienced significant bloating reduction compared with those receiving a traditional diet, OR = 0.32 (Table 3), and there was no significant heterogeneity (Table 3, Figure 2C). Analysis of publication bias by the trim and fill method did not lead to the exclusion of any paper (Figure 2D). Egger’s test was not significant (Table 3).

3.1.3. Stool Consistency: There was no significant difference between treatments (effect size (ES) = 0.24, Table 3); statistical heterogeneity was moderate but not significant (Figure 3A). Analysis of publication bias with the trim and fill method failed to exclude any paper (Figure 3B). Egger’s test was not significant (Table 3).

3.1.4. Stool Frequency: There was a significant difference between treatments for this outcome (ES = −0.54; p < 0.001). There was no statistical heterogeneity (Table 3, Figure 3C). Analysis of publication bias with the trim and fill method failed to exclude any paper (Figure 3D). Egger’s test was not significant (Table 3).

3.2. Low-FODMAP Diet vs. Medium/High-FODMAP Diet: The primary studies (k = 3 RCTs) compared patients managed with a low-FODMAP diet and patients receiving a high/medium-FODMAP diet. Their main characteristics are listed in Table 1. This set of studies examined two outcomes: reduction of abdominal pain and of bloating.

3.2.1. Abdominal Pain: Significantly reduced abdominal pain was described by patients receiving a low-FODMAP diet compared with those receiving a high-FODMAP diet (OR = 0.17). There was no statistical heterogeneity (Table 3). Analysis of publication bias with the trim and fill method failed to exclude any paper (Figure 4B). Finally, Egger’s test was not significant (Table 3).

3.2.2. Bloating: The patients receiving a low-FODMAP diet reported a significant reduction of bloating compared with those given a high-FODMAP diet (OR = 0.13); statistical heterogeneity was moderate but not significant (Table 3, Figure 4C). Analysis of publication bias by the trim and fill method did not lead to the exclusion of any paper (Figure 4D). Egger’s test was not significant (Table 3).

3.3. Cohort Studies: The primary studies (k = 6) compared baseline versus post-treatment data in patients treated with a low-FODMAP diet (Table 2). Two outcomes were assessed in this set: reduction of abdominal pain and reduction of bloating. Meta-regressions were performed for both outcomes using gender, age, and year of publication.

3.3.1. Abdominal Pain: Pain after treatment was significantly reduced compared with baseline in these patients (ES = −0.59). There was no statistical heterogeneity (Table 3, Figure 5A). Analysis of publication bias by the trim and fill method did not result in the exclusion of any paper (Figure 5B). Egger’s test was not significant (Table 3). The meta-regression lines for age (p = 0.652), gender (p = 0.817), and year of publication (p = 0.543) were not significant (Figure 5C–E).

3.3.2. Bloating: Significantly reduced bloating was reported by patients after treatment (ES = −0.64). There was no statistical heterogeneity (Table 3, Figure 6A). Analysis of publication bias by the trim and fill method did not lead to the exclusion of any paper (Figure 6B). Finally, Egger’s test was not significant (Table 3). The meta-regression lines for age (p = 0.808), gender (p = 0.747), and year of publication (p = 0.804) were not significant (Figure 6C–E).

Objective: To systematically evaluate the efficacy and safety of Modified Tongxie Yaofang (M-TXYF) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D).

Method: Electronic databases including PubMed, Springer Link, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang, and Chinese Scientific Journals Database (VIP) were conducted from their inception through May 11, 2017 without language restrictions. Primary and secondary outcomes were estimated by 95% confidence intervals (CI). RevMan 5.3 and the Cochrane Collaboration’s risk of bias tool were analyzed for this meta-analysis.

Results: Twenty-three literatures with a total of 1972 patients were included for the meta-analysis. The overall risk of bias evaluation was low. The pooled odds ratio showed that M-TXYF was significantly superior to routine pharmacotherapies (RP) in clinical therapeutic efficacy (OR 4.04, 95% CI 3.09, 5.27, P < 0.00001, therapeutic gain = 17.6%, number needed to treat (NNT) = 5.7). Moreover, compared with RP, M-TXYF showed that it can significantly reduce the scores of abdominal pain (standardized mean difference (SMD) -1.27; 95% CI -1.99, -0.56; P = 0.0005), abdominal distention (SMD -0.37; 95% CI -0.73, -0.01; P = 0.09), diarrhea (SMD -1.10; 95% CI -1.95, -0.25; P = 0.01), and frequency of defecation (SMD -1.42; 95% CI -2.19, -0.65; P = 0.0003). The differences of the adverse events between experiment and control groups had no statistical significance.

Conclusion: This meta-analysis indicated that M-TXYF could be a promising Chinese herbal formula in treating IBS-D. However, considering the lack of higher quality of randomized controlled trials (RCTs), highly believable evidences should be required.

A total of 1,506 relevant studies were identified based on computer search. Both investigators agreed on the results of inclusion criteria and showed detailed screening process for study identification and selection in Fig 1. Finally, twenty-three RCTs met the inclusion criteria for the meta-analysis. Literature characteristics are described in Table 1.

A description of the assessment for methodological quality is shown in Table 2. In this systematic review, nineteen trials described how patients were randomly assigned into the experiment groups and the control groups (fifteen used a random number table, two used a block randomization, one used a random grouping table, and one used a stratified block randomization ). However, the remaining four studies did not report the specific randomization technique. In addition, only the Peng et al. study used a single-blind. Only the Gao et al. study used a double-blind and double-dummy. As for allocation concealment, only the Peng et al. study and the Tao et al. study used lightproof envelopes. In addition, eight trials reported follow-up after treatment. Although withdrawals and dropouts were mentioned in seven studies, only the Peng et al. study conducted intention-to-treat (ITT) analysis. The Chen et al. study used full analysis sets (FAS). The Gao et al. study conducted full analysis set (FAS), per-protocol population set (PPS) and safe set (SS). However, the remaining studies did not conduct intention-to-treat (ITT) analysis for the cases of dropouts. In a word, because of lacking specific information, it cannot be determined whether implementations were adequately performed in the process of random sequence generation, blinding or allocation concealment. Therefore, the validity of this review in Fig 2 could be regarded as high risk.

Primary outcome measurement: clinical therapeutic efficacy / Comparison of clinical therapeutic efficacy: A total of 23 included studies reported the efficacy, which included 1972 patients where 1052 and 920 participants were respectively assigned to M-TXYF and RP. Based on the “Guiding Principle for Clinical Research of New Drugs of TCM”, clinical therapeutic efficacy was calculated in the comprehensive efficacy index (CEI): CEI(%) = (the numbers of patients whose clinical symptom improved after intervention divide total numbers of patients) × 100%.

Subgroup analysis: Because of variability in evaluating point of clinical therapeutic efficacy, we conducted subgroup analysis among studies using different interventions of Pinaverium bromide tablets (PBT), PBT + another RP (including Montmorillonite powder, Trimebutine maleate, Bacillus licheniformis, Loperamide, Miyarisam, Glutamine compound enteric capsule, Live combined bifidobacterium, Lactobacillus and enterococcus), and another RP. Compared with the control groups, the experiment groups were positive effects on the improvement of clinical symptoms for PBT (OR 4.14; 95% CI 2.98, 5.75; P < 0.00001) in fifteen trials, PBT + another RP (OR 4.14; 95% CI 1.67, 10.07; P = 0.002) in three trials, another RP (OR 3.73; 95% CI 2.20, 6.34; P < 0.00001) in five trials, and an overall efficacy (OR 4.04; 95% CI 3.09, 5.27; P < 0.00001) in Fig 3. In addition, the results in Table 3 showed that 90.3% of treatment group participants had a clinical effectiveness, which was superior to 72.7% of control group participants (therapeutic gain = 17.6% with NNT = 5.7). Potential publication bias (Begg’s test, P = 0.009) was identified by observing the asymmetrical plot in Fig 4.

Secondary outcome measurements / Abdominal pain score: Among the included studies, fourteen reported the improvement of abdominal pain. However, owing to the existence of substantial heterogeneity (χ2 = 352.05, P < 0.00001, I2 = 96%), a random effect model was applied to estimating pooled effect sizes. Furthermore, the forest plot in Fig 5 showed that the reduction of abdominal pain score in experiment groups was more remarkable than that in control groups (SMD -1.27; 95% CI -1.99, -0.56; P = 0.0005).

Abdominal distention score: Eight studies reported abdominal distention score. A random effect model was conducted because of significant heterogeneity (χ2 = 32.78, P < 0.0001, I2 = 79%). However, the result of meta-analysis in Fig 6 showed that M-TXYF had no statistically significant differences in alleviation for abdominal distention compared with RP (SMD -0.37; 95% CI -0.73, -0.01; P = 0.09).

Diarrhea score: Of all the included studies, eight reported the diarrhea score. A model of random effect was conducted to estimate pooled effect sizes because of significant heterogeneity (χ2 = 133.95, P < 0.00001, I2 = 95%). Treatment groups in Fig 7 showed more significant improvement of diarrhea than control groups (SMD -1.10; 95% CI -1.95, -0.25; P = 0.01).

Frequency of defecation score: In the included trials, seven described the situation of defecation’s frequency. Random-effect meta-analysis in Fig 8 indicated that M-TXYF had positive effects on frequency of defecation changes (χ2 = 100.96, P < 0.00001, I2 = 94%) (SMD -1.42; 95% CI -2.19, -0.65; P = 0.0003).

BSS score: Two included trials applied bowel symptom severity scale (BSS) to estimate the severity of IBS-D symptoms. Considering the lack of enough numbers of literatures, the overall BSS score were only qualitatively analyzed in order to avoid inaccurate and unreliable outcomes. But in improving bowel symptom severity, the experiment groups had potentially superior to the control groups.

QOL scale: Four qualified literatures reported health-related quality of life (QOL). One used the Chinese version of the short form 36 (SF-36) which was validated in Hong Kong. Another one used QOL scale whose contents contained psychological and physical dimensions, and social adaptability. The remaining two studies used IBS-QOL which was authorized by Patrick et al.. Although the four literatures elaborated different ingredients of QOL scale, they all showed that M-TXYF could significantly improve health-related QOL.

Safety evaluation: Twelve studies assessed the safety of M-TXYF in the course of treatment. One trial reported 2 cases of nausea occurred in the experiment group and 10 cases of adverse reactions (4 for nausea, 4 for local skin rash, and 2 for abdominal discomfort) occurred in the control group. In addition, although one trial reported 4 cases of side effects (2 for constipation, 1 for nausea, and 1 for dry mouth) occurred in the control group, all of these side effects spontaneously disappeared after the treatment session. Besides, the Fang study reported 1 case of nausea occurred in the experiment group and 6 cases of adverse effects (2 for constipation, 2 for nausea, and 2 for skin rash) occurred in the control group. But these side effects did not have impact on the experimental process. In addition, nine trials had no adverse reactions during M-TXYF treatment.