Prophylactic effects of probiotics or synbiotics on postoperative ileus after gastrointestinal cancer surgery: A meta-analysis of randomized controlled trials.

BACKGROUND: Postoperative ileus is a major problem following gastrointestinal cancers surgery, several randomized controlled trials have been conducted investigating the use of probiotics or synbiotics to reduce postoperative ileus, but their findings are controversial.
OBJECTIVE: We conducted a meta-analysis to determine the effect of probiotics or synbiotics on early postoperative recovery of gastrointestinal function in patients with gastrointestinal cancer.
METHODS: The Embase, Cochrane Library, PubMed, and Web of Science databases were comprehensively searched for randomized controlled trials (RCTs) that evaluated the effects of probiotics or synbiotics on postoperative recovery of gastrointestinal function as of April 27, 2021. Outcomes included the time to first flatus, time to first defecation, days to first solid diet, days to first fluid diet, length of postoperative hospital stay, incidence of abdominal distension and incidence of postoperative ileus. The results were reported as the mean difference (MD) and relative risk (RR) with 95% confidence intervals (CI).
RESULTS: A total of 21 RCTs, involving 1776 participants, were included. Compared with the control group, probiotic and synbiotic supplementation resulted in a shorter first flatus (MD, -0.53 days), first defecation (MD, -0.78 days), first solid diet (MD, -0.25 days), first fluid diet (MD, -0.29 days) and postoperative hospital stay (MD, -1.43 days). Furthermore, Probiotic and synbiotic supplementation reduced the incidence of abdominal distension (RR, 0.62) and incidence of postoperative ileus (RR, 0.47).
CONCLUSION: Perioperative supplementation of probiotics or synbiotics can effectively promote the recovery of gastrointestinal function after gastrointestinal cancer surgery.

Introduction

Gastrointestinal cancers account for about 25% of new cancer cases worldwide and cause more than 35% of cancer-related deaths [1]. Surgery is an essential treatment for gastrointestinal cancer. Postoperative ileus is an inevitable and most common complication of gastrointestinal surgery, with up to 30% of patients suffering from postoperative ileus [2-4]. Postoperative ileus refers to the delayed recovery of gastrointestinal function after surgery, with clinical manifestations of abdominal distension, abdominal pain, vomiting, and delayed defecation of exhaust, leading to prolonged hospital stay and increased morbidity [4-7]. Postoperative ileus is a significant financial burden for patients, adding more than 1,000,000,000 dollars in additional medical costs annually in the United States [8]. Although a number of strategies have been explored for the prevention of postoperative ileus, such as gum chewing, intravenous lidocaine, and preoperative activities, their efficacy remains controversial [5].

Probiotics are living microorganisms that are beneficial to the human body when supplemented in appropriate amounts [9]. Prebiotics are substances, such as inulin and fructooligosaccharides that promote beneficial gut microbe growth [10]. Probiotics combined with prebiotics are called synbiotics [9]. Historically, probiotics and synbiotics have been widely used in the adjuvant treatment of gastrointestinal diseases [11]. In recent years, a large number of studies have found that probiotics and synbiotics can reduce the risk of infection complications after abdominal surgery [12]. In addition, probiotics and synbiotics could also promote gastrointestinal motility [13]. Probiotics and synbiotics are inexpensive, readily available, and safe [14]. Based on these findings, probiotics and synbiotics may be potential strategies to promote recovery of gastrointestinal function after gastrointestinal cancer surgery and to reduce the incidence of postoperative ileus. However, clinical studies have shown conflicting results [15, 16]. Therefore, it is extremely important to establish strong evidence to determine whether perioperative probiotics or synbiotics can prevent postoperative ileus.

Hence, we systematically collected evidence from current randomized controlled trails (RCTs) and performed a meta-analysis to determine the effect of probiotics or synbiotics on early postoperative recovery of gastrointestinal function in patients with gastrointestinal cancer.

Materials and methods

The meta-analysis is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [17] (see S1 Checklist, PRISMA checklist, which contains PRISMA 2009 checklist).

Search strategy

Systematic literature searches were conducted on Web of Science, Cochrane Library, Embase, and PubMed databases with no filters until April 27, 2021. The search terms were: (synbiotics OR prebiotic OR probiotics OR probiotic OR prebiotics OR synbiotic) AND (operation OR surgery) AND (cancer OR neoplasm OR carcinoma OR tumour) (S1 Table). Additionally, the reference lists of related reviews were also searched to reduce omissions.

Study selection

Studies that met the following criteria were included: (1) study design: RCTs, (2) participants: gastrointestinal cancer patients undergoing surgery, (3) intervention: intervention with probiotics or synbiotics, (4) comparison: the control group received the standard treatment or a placebo, and (5) the outcomes included any of the following: time to first flatus, time to first defecation, postoperative ileus, days to first solid diet, abdominal distension, days to first fluid diet, and length of postoperative hospital stay. Duplicate studies, reviews, abstracts, non-randomized trails, animal studies, letters, and case reports were excluded.

Data extraction

The first author, gender, year, primary disease, sample size, type of surgery, type of study, age, treated days, intervention, control group data, and outcomes were extracted from each study. If the essential data could not be obtained from the article, the corresponding author was contacted to try to obtain the missing data.

Quality assessment

Risk of bias for eligible studies was assessed by the ROB-2 tool available in the Cochrane Handbook, including the following domains: (1) Randomization process, (2) Deviations from intended interventions, (3) Missing outcome data, (4) Measurement of the outcome, (5) Selection of the reported result, and (6) Overall. Literature retrieval, selection of article, data extraction, and risk of bias assessment were performed independently by two authors (Gang Tang and Jie Tao). If there was a disagreement between the authors, it was discussed and resolved with a third author (Wang Huang).

Statistical analysis

For continuous data, the mean differences (MD) with 95% confidence intervals (CIs) were calculated. Relative risks (RRs) were calculated for dichotomous variable data [18]. The I2 statistic was used to assess the magnitude of heterogeneity between studies; The random effect model was used in all quantitative analyses, and the fixed effect model was selected only when heterogeneity was low [19]. For result robustness, the one-study exclusion test was used to investigate the influence of each study on the total effect size. Subgroup analysis was performed by intervention type (probiotics or synbiotics). Egger’s test was performed using Stata 12.0 (Stata Corp., College Station, TX, USA) to assess potential publication bias. In addition, funnel plots were used when the number of included studies > 10. All statistical analyses were performed using Review 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration 2014; Copenhagen, Denmark). P <0.05 was considered significant.

GRADE assessment

To grade the quality of evidence, a GRADE assessment was performed through GRADEpro online tools (https://gradepro.org/). GRADE assessed the evidence as four levels: very low, low, medium, and high. The two researchers (Gang Tang and Jie Tao) independently assess the certainty of the evidence, and if there was dispute, they would discuss and resolve it.

Results

Literature retrieval

Our search strategy yielded 1,992 records and 463 duplicates were removed. 1479 of the results were excluded after reading the headings and abstracts, and the remaining 50 records were evaluated for the full text. Finally, 21 eligible studies [16, 20–39] were included. The flow chart of literature retrieval is shown in Fig 1.

Fig 1

Flow chart of literature search and screening.

Study characteristics

Between 2005 and 2020, 21 studies were published with 1776 total participants (875 in the intervention group and 901 in the control group). Twelve studies [16, 20, 22, 25, 29, 30, 32, 35–39] used only probiotics, and nine [21, 23, 24, 26–28, 31, 33, 34] used synbiotics. The indications for surgery were colorectal cancer, gastric cancer, liver cancer, gallbladder cancer, esophageal cancer and periampullary cancer. The characteristics of eligible studies are detailed in S2 Table.

Ten of the studies [16, 22, 23, 27–29, 31, 32, 34, 36] conducted an appropriate randomization process. Deviations from intended interventions were evaluated as a low bias risk in six studies [16, 20, 22, 31, 34, 36]. Missing outcome data, measurement of the outcome, and selection of the reported result in all studies were assessed as a low bias risk (Fig 2). The overall risk of 10 studies [16, 22, 23, 27–29, 31, 32, 34, 36] was assessed as low risk of bias.

Fig 2

Risk of bias for each included study.

(A), risk of bias summary. (B), risk of bias graph.

Meta-analysis

Time to first flatus

Eight RCTs [20, 24, 28, 32, 33, 37–39] (617 patients) reported on time to first flatus. Probiotics or synbiotics supplementation was associated with a significant reduction in time to first flatus (MD, -0.53 days; 95% CI, -0.75, -0.30; P < 0.00001) (Fig 3), with significant heterogeneity (I2 = 73%, P = 0.0005). The results of subgroup analysis showed that both probiotics (MD, -0.70 days; 95% CI, -1.10, -0.30; P = 0.0006) alone and synbiotics (MD, -0.34 days; 95% CI, -0.58, -0.10; P = 0.006) supplementation were associated with shorter first exhaust time.

Fig 3

Effect of probiotics or synbiotics supplementation on time to first flatus.

Time to first defecation

Seven studies [20, 22, 24, 28, 29, 32, 39] measured time to first defecation as an outcome. Compared with the control group, probiotics or synbiotics significantly reduced the time to first defecation, with significant heterogeneity (MD, -0.78 days; 95% CI, -1.27, -0.28; P = 0.002; I2 = 86%, P < 0.00001) (Fig 4). Subgroup analysis indicated that this benefit was observed only in the subgroup supplemented with probiotics alone (MD, -0.99 days; 95% CI, -1.61, -0.37).

Fig 4

Effect of probiotics or synbiotics supplementation on time to first defecation.

Days to first solid diet

Five studies [22, 28, 29, 32, 39] reported data for days to first solid diet, pooled results showed that probiotics or synbiotics supplementation significantly shortened the days to first solid diet (MD, -0.25 days; 95% CI, -0.39, -0.12; P = 0.0002) (Fig 5). In addition, no significant heterogeneity was shown between RCTs (I2 = 0%, P = 0.94).

Fig 5

Effect of probiotics or synbiotics supplementation on days to first solid diet.

Days to first fluid diet

Three RCTs [22, 29, 32] mentioned days to first fluid diet. Probiotics or synbiotics significantly shortened the days to first fluid diet (MD, -0.29 days; 95% CI, -0.47, -0.11; P = 0.001) (Fig 6), and no significant heterogeneity was observed between the three studies (I2 = 0%, P = 0.83).

Fig 6

Effect of probiotics or synbiotics supplementation on days to first fluid diet.

Length of postoperative hospital stay

Twelve RCTs [16, 21–23, 26, 29–33, 37] with a total of 440 participants were in the probiotics or synbiotics group and 440 in the control. The combined result favored probiotics or synbiotics supplementation, with a MD of 1.43 days reduction (MD, -1.43 days; 95% CI, -2.29, -0.58; P = 0.001; I2 = 67%; Fig 7). Subgroup analysis showed that both probiotics (MD, -1.06 days; 95% CI, -2.05, -0.07; P = 0.04) and synbiotics (MD, -2.34 days; 95% CI, -4.29, -0.39; P = 0.02) supplementation reduced length of postoperative hospital stay.

Fig 7

Effect of probiotics or synbiotics supplementation on length of postoperative hospital stay.

Postoperative ileus

Of the 21 eligible RCTs, four studies [25, 27, 35, 36] (559 participants) reported findings on postoperative ileus, the combined total effect size showed that supplementation with probiotics or synbiotics significantly reduced the incidence of postoperative ileus (RR, 0.47; 95% CI, 0.24, 0.91, P = 0.02; I2 = 9%, P = 0.35) (Fig 8).

Fig 8

Effect of probiotics or synbiotics supplementation on the incidence of postoperative ileus.

Abdominal distension

Five RCTs [20, 22, 29, 32, 33] presented data on incidence of abdominal distension. Supplementation with probiotics or synbiotics was associated with a significant reduction in the incidence of postoperative abdominal distension (RR, 0.62; 95% CI, 0.47, 0.81; P = 0.0004) (Fig 9), with low heterogeneity (I2 = 0%, P = 0.97).

Fig 9

Effect of probiotics or synbiotics supplementation on the incidence of postoperative abdominal distension.

Sensitivity analysis

The results of the sensitivity analysis indicated that excluding any one study did not affect the total effect size of the time to first flatus, time to first defecation, days to first solid diet, length of postoperative hospital stay and incidence of abdominal distension. The overall effect size for the days to first fluid diet changed when the study by Liu et al. [22] (MD, -0.28 days; 95% CI, -0.60, 0.04; P = 0.09) was excluded. The overall effect size of the incidence of postoperative ileus was influenced by the study of Bajramagic et al. [35] (RR, 0.66; 95% CI, 0.32, 1.37, P = 0.26).

Publication bias

Egger’s test results did not show potential publication bias of the time to first flatus (P = 0.214), time to first defecation (P = 0.754), days to first solid diet (P = 0.609), days to first fluid diet (P = 0.991), length of postoperative hospital stay (P = 0.970), incidence of abdominal distension (P = 0.530) and incidence of postoperative ileus (P = 0.265). Visual inspection of the funnel plot (length of postoperative hospital stay) identified basically symmetric (Fig 10).

Fig 10

Funnel plot of effect of probiotics or synbiotics supplementation on the length of postoperative hospital stay.

GRADE analysis

We evaluated the quality of evidence in this study (Fig 11). A part of the evidence (the time to first flatus, days to first fluid diet, incidence of abdominal distension and incidence of postoperative ileus) was in a medium level, one (length of postoperative hospital stay) was very low, one (the time to first defecation) was low, one (days to first solid diet) was high.

Fig 11

Grade evidence synthesis and summary of findings.

Discussion

Postoperative gastrointestinal function, as the core part of the accelerated recovery of patients with gastrointestinal cancer undergoing surgery, has important clinical significance and has been paid close attention by surgeons [40]. To our knowledge, this is the first meta-analysis to evaluate the effect of probiotics or synbiotics on gastrointestinal function recovery after gastrointestinal cancer surgery. Evidence from this meta-analysis was based on 21 RCTs with 1776 participants. The results showed that peri-operative probiotics or synbiotics supplementation signifcantly reduced the time to first flatus, time to first defecation, days to first solid diet, days to first fluid diet and length of postoperative hospital stay. The time to first flatus and time to first defecation are the key to evaluate gastrointestinal dysfunction and postoperative ileus. They are generally considered to be the relief of postoperative ileus, and are also important indicators to evaluate the efficacy of intervention methods [4]. The results of subgroup analysis showed that either probiotics alone or synbiotics alone could shorten the time to first exhaust and first defecation. In addition, probiotics or prebiotics could also reduce the incidence of postoperative abdominal distension and postoperative ileus. This study has important clinical significance because our meta-analysis provides clear evidence that probiotics or synbiotics could promote gastrointestinal recovery normality after surgery for gastrointestinal cancer. Hence, probiotics or synbiotics are potential strategies that clinicians should consider in the prevention of postoperative ileus.

The mechanism of postoperative ileus is not clear and may involve the interaction of many factors [2], inhibition of gastrointestinal motility caused by surgical overstimulation of the sympathetic nerve may be the most important factor [41]. In addition, substance P and nitric oxide secreted by the enteric nervous system also prolong the duration of postoperative ileus. Furthermore, surgery stimulates the inflammatory cascade, releasing a large number of inflammatory mediators, such as interleukin-6, interleukin-1, monocytechemoattractantprotein-1 and cell adhesion molecule-1, which damage intestinal muscles and further inhibit the recovery of gastrointestinal function [2, 41]. Some drugs have also been associated with increased the risk of ileus after surgery [2]. Probiotics or synbiotics are an alternative therapy widely used in cancer patients to prevent postoperative infection, relieve symptoms and improve quality of life, with beneficial effects in a variety of gastrointestinal diseases having been demonstrated [42]. Peri-operative supplementation with probiotics or synbiotics could modulate local and systemic immune homeostasis, reduce inflammatory responses, and reduce concentrations of pro-inflammatory factors, tumor necrosis factor-α, interleukin-6, C-reactive protein, and nitric oxide which could aggravate postoperative ileus by ameliorating operationally induced intestinal flora dysregulation [42-46]. In addition, Schmitter et al. found that probiotics significantly reduced the release of interleukin-6, interleukin-8, and prostaglanin E2 from monocytes compared with placebo [47]. Studies have shown that dendritic cells in the gastrointestinal tract can interact with intestinal nerve cells and intestinal microorganisms. Probiotics or synbiotics may stimulate nerve cells to promote gastrointestinal function recovery by regulating intestinal microorganisms [42].

Several excluded clinical studies have also supported the beneficial effects of probiotics or synbiotics on postoperative ileus. A non-RCT study by Aisu et al. [48] showed that perioperative probiotics supplementation significantly reduced the time to first exhaust and first feeding. Kotzampassi et al. [49] found that a capsule containing four probiotics significantly shortened the time to first defecation in patients undergoing colorectal surgery, compared with a placebo. In addition, Xu et al. [50] demonstrated that early use of synbitin after colon cancer surgery can improve immune function, reduce inflammatory response, and promote gastrointestinal function recovery.

This study has several strengths. First, only RCTs were included in our meta-analysis in order to synthesize the strongest evidence. Second, this study conducted a comprehensive literature search to reduce bias. Furthermore, we used advanced statistical methods to find no potential publication bias. Finally, we confirmed the robustness of our results (including time to first exhaust, time to first defecate, days to first fluid diet, incidence of abdominal distension and length of hospital stay) through sensitivity analysis.

Our meta-analysis also had several limitations. First, several studies with small sample sizes were included. Second, some outcome measures (incidence of postoperative ileus and incidence of postoperative abdominal distension) were quantitatively synthesized based on a small number of studies. Third, Significant heterogeneity was observed in our study, which may be related to significant differences in type of surgery (radical colorectomy, liver resection, esophagectomy, colorectal cancer resection, gastrectomy and pancreatoduodenectomy), duration of probiotics or synbiotics supplementation (from 3 days to 28 days), species of probiotics or synbiotics and dose of probiotics or synbiotics. Future research should explore the specific species of probiotics or synbiotics with the greatest benefit for gastrointestinal function recovery, as well as the most appropriate course and dose of probiotics or synbiotics supplementation. Finally, this study only included patients with gastrointestinal cancer who underwent elective surgery, so our findings may not be generalizable to patients undergoing emergency surgery.

Conclusions

In conclusion, our study showed that perioperative supplementation of probiotics or synbiotics can effectively promote the recovery of gastrointestinal function after gastrointestinal cancer surgery, including shorting the time to first flatus, time to first defecation, days to first solid diet, days to first fluid diet and length of postoperative hospital stay, and reducing the incidence of postoperative abdominal distention and postoperative ileus. But these conclusions need to be treated with caution, given some limitations that cannot be ignored. High-quality, large-sample RCTs are necessary to confirm the benefit of probiotics or synbiotics supplementation for gastrointestinal function recovery after gastrointestinal cancer surgery.

PRISMA checklist.

(DOC)

Click here for additional data file.

Electronic search strategy.

(DOC)

Click here for additional data file.

Characteristics of 21 eligible studies.

CFU: colony forming units; C: Control group; DB: Double blind; I: Intervention group; GOS: galacto-oligosaccharides; PD: pancreatoduodenectomy; N: not available; RCT: randomized controlled trial; SC: standard care; TF: time to first flatus; TD: time to first defecation; LOP: Length of postoperative hospital stay; PI: Postoperative ileus; DS: Days to first solid diet; AB; abdominal distension; DF: days to first fluid die.

(DOC)

Click here for additional data file.

8 Sep 2021

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Laura Pasin

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that this manuscript is a systematic review or meta-analysis; our author guidelines therefore require that you use PRISMA guidance to help improve reporting quality of this type of study. Please upload copies of the completed PRISMA checklist as Supporting Information with a file name “PRISMA checklist

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for your work.

The manuscript is interesting and well written.

As underlined by authors in the discussion, the two main limitations are the heterogeneity of included studies ( very different types of surgery) and the small sample size of included studies.

I would like to ask to the authors if they performed a trial sequential analysis, to better evaluate the results of their study.

Thank you

Reviewer #2: GENERAL COMMENT

Thanks for the opportunity to review this article. The authors conducted a systematic review and meta-analysis of randomized controlled trials investigating the effect of probiotics or synbiotics on early postoperative recovery of gastrointestinal function in patients with gastrointestinal cancer. They found that perioperative supplementation of probiotics or synbiotics can effectively promote the recovery of gastrointestinal function after gastrointestinal cancer surgery. The research question is clinically relevant and original. However, I would have the following major comments:

- I would suggest the authors to perform an extensive English language editing of the manuscript.

- Further efforts should be carried out to explore the reasons for the moderate-high heterogeneity detected among the studies, as the authors appropriately pointed out in the limitations section. This would significantly strengthen the authors’ findings.

- The Risk of Bias tool the authors employed is not the most recent one. The recommended tool for assessing risk of bias of RCTs is the RoB 2 (https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2?authuser=0). Please provide the risk of bias assessment by using this tool.

- A GRADE assessment is very important to better inform the reader about the overall certainty of evidence. Please perform a GRADE assessment. Online tools are available for this, e.g., https://gradepro.org/.

MINOR COMMENTS

Line 77: “Our meta-analysis was conducted based on”

The meta-analysis is reported based on PRISMA Checklist, rather than conducted based on it. Please modify accordingly.

Line 81: “Additionally, the reference lists of related reviews were also searched”

It seems to me that this sentence should be placed afterwards or removed, considering the last sentence of the paragraph.

Lines 110-111: “the random-effects model was selected when I^2 was >50 %”

It is not recommended to choose the model based on the I^2 value. A random-effects model should be applied regardless of the I^2, unless the authors anticipate there to be very small heterogeneity. Otherwise, sensitivity analyses with different I^2 thresholds should be performed.

Line 113: “Egger's test”

Along with the Egger’s test, should there be a significant number of included studies (> 10), funnel plots should be provided as well.

Lines 145-146: “and there was significant heterogeneity (I^2 = 55.8%, P = 0.13) between subgroups. In addition, heterogeneity was significantly reduced in the synbiotics subgroup (I^2 = 27%, P = 0.25)”

In my opinion, the authors should report that the p-value allows to conclude that there was no subgroup difference. The difference in heterogeneity between the groups cannot really be compared and stated as significant.

Line 152: “with significant heterogeneity”

The authors should provide the I^2 and the p-value relative to the I^2 test, like for the time to first flatus outcome. The same should be considered for Lines 178-179.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

26 Sep 2021

Replies to the Reviewer

Thank you very much for taking time to review our manuscript. We have carefully read your comments and suggestions, which have been of great help. We have revised the manuscript according to the comments and responded point-by-point to the comments, as listed below. Additionally, we have highlighted all revised text.

Reviewer #1: Thank you for your work.

The manuscript is interesting and well written.

As underlined by authors in the discussion, the two main limitations are the heterogeneity of included studies ( very different types of surgery) and the small sample size of included studies.

I would like to ask to the authors if they performed a trial sequential analysis, to better evaluate the results of their study.

Thank you

Answer: Thanks again to the reviewer, we did not performe a trial sequential analysis in our meta-analysis. This is the first meta-analysis on this topic, so we did not consider using a trial sequential analysis when making our study protocol.

Reviewer #2: GENERAL COMMENT

Thanks for the opportunity to review this article. The authors conducted a systematic review and meta-analysis of randomized controlled trials investigating the effect of probiotics or synbiotics on early postoperative recovery of gastrointestinal function in patients with gastrointestinal cancer. They found that perioperative supplementation of probiotics or synbiotics can effectively promote the recovery of gastrointestinal function after gastrointestinal cancer surgery. The research question is clinically relevant and original. However, I would have the following major comments:

- I would suggest the authors to perform an extensive English language editing of the manuscript.

Answer: With the help of the Taylor & Francis Editing Services, we perform an extensive English language editing of the manuscript. The major revisions are highlighted in the manuscript, and the minor revisions made to fix grammatical errors and improve expressions do not affect the results.

- Further efforts should be carried out to explore the reasons for the moderate-high heterogeneity detected among the studies, as the authors appropriately pointed out in the limitations section. This would significantly strengthen the authors’ findings.

Answer: Thanks for the reviewer's suggestion. Due to the significant heterogeneity, we are prepared to conduct a subgroup analysis to explore the source of heterogeneity. As we mentioned in the discussion, different surgical methods, differences dose and species of probiotics or synbiotics, and different courses of treatment may be the source of heterogeneity. However, due to the limited number of studies, we were unable to conduct subgroup analysis of these factors. In the future, we will conduct more detailed analyses with more studies.

In the discussion section of the manuscript : “Significant heterogeneity was observed in our study, which may be related to significant differences in type of surgery (radical colorectomy, liver resection, esophagectomy, colorectal cancer resection, gastrectomy and pancreatoduodenectomy), duration of probiotics or synbiotics supplementation (from 3 days to 28 days), species of probiotics or synbiotics and dose of probiotics or synbiotics. Future research should explore the specific species of probiotics or synbiotics with the greatest benefit for gastrointestinal function recovery, as well as the most appropriate course and dose of probiotics or synbiotics supplementation.”

- The Risk of Bias tool the authors employed is not the most recent one. The recommended tool for assessing risk of bias of RCTs is the RoB 2 (https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2?authuser=0). Please provide the risk of bias assessment by using this tool.

Answer: As suggested by reviewers, we have used the latest tools for bias evaluation (figure 2).

“Risk of bias for eligible studies was assessed by the ROB-2 tool available in the Cochrane Handbook, including the following domains: (1) Randomization process, (2) Deviations from intended interventions, (3) Missing outcome data, (4) Measurement of the outcome, (5) Selection of the reported result, and (6) Overall.”

“Ten of the studies [22, 23, 27-29, 31-33, 35, 37] conducted an appropriate randomization process. Deviations from intended interventions were evaluated as a low bias risk in six studies [20, 22, 31, 32, 35, 37].Missing outcome data, measurement of the outcome, and selection of the reported result in all studies were assessed as a low bias risk (Fig 2). The overall risk of 10 studies [22, 23, 27-29, 31-33, 35, 37] was assessed as low risk of bias.”

- A GRADE assessment is very important to better inform the reader about the overall certainty of evidence. Please perform a GRADE assessment. Online tools are available for this, e.g., https://gradepro.org/.

Answer: Thanks you for your comments, we have performed a GRADE assessment and revised the manuscript. As follow: “ GRADE Assessment

To grade the quality of evidence, a GRADE assessment was performed through GRADEpro online tools (https://gradepro.org/). GRADE assessed the evidence as four levels: very low, low, medium, and high. The two researchers (Gang Tang and Jie Tao) independently assess the certainty of the evidence, and if there was dispute, they would discuss and resolve it.”

“GRADE analysis

We evaluated the quality of evidence in this study (Fig 11). A part of the evidence (the time to first flatus , days to first fluid diet , incidence of abdominal distension and incidence of postoperative ileus) was in a medium level, one (length of postoperative hospital stay) was very low, one (the time to first defecation) was low, one (days to first solid diet) was high”

MINOR COMMENTS

Line 77: “Our meta-analysis was conducted based on”

The meta-analysis is reported based on PRISMA Checklist, rather than conducted based on it. Please modify accordingly.

Answer: Thanks to the reviewers for pointing out these details, we have revised them in the manuscript .

As follow: “The meta-analysis is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement”

Line 81: “Additionally, the reference lists of related reviews were also searched”

It seems to me that this sentence should be placed afterwards or removed, considering the last sentence of the paragraph.

Answer: As suggested by the reviewer, we deleted this sentence.

Lines 110-111: “the random-effects model was selected when I^2 was >50 %”

It is not recommended to choose the model based on the I^2 value. A random-effects model should be applied regardless of the I^2, unless the authors anticipate there to be very small heterogeneity. Otherwise, sensitivity analyses with different I^2 thresholds should be performed.

Answer: We revised the manuscript as suggested by the reviewers. As follow: “The random effect model was used in all quantitative analyses, and the fixed effect model was selected only when heterogeneity was low”

Line 113: “Egger's test”

Along with the Egger’s test, should there be a significant number of included studies (> 10), funnel plots should be provided as well.

Answer: We have made the following revisions.

“In addition, funnel plots were used when the number of included studies > 10.”

“Visual inspection of the funnel plot (length of postoperative hospital stay) identified basically symmetric (Fig 10).”

Lines 145-146: “and there was significant heterogeneity (I^2 = 55.8%, P = 0.13) between subgroups. In addition, heterogeneity was significantly reduced in the synbiotics subgroup (I^2 = 27%, P = 0.25)”

In my opinion, the authors should report that the p-value allows to conclude that there was no subgroup difference. The difference in heterogeneity between the groups cannot really be compared and stated as significant.

Answer: We fully agree with the reviewer's point of view, and we have deleted this sentence

Line 152: “with significant heterogeneity”

The authors should provide the I^2 and the p-value relative to the I^2 test, like for the time to first flatus outcome. The same should be considered for Lines 178-179.

Answer: We revised the manuscript based on suggestions from reviewers, and we have provided the I^2 and the p-value relative to the I^2 test.

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

17 Feb 2022

Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled Trials

PONE-D-21-20250R1

Dear Dr. wei,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Laura Pasin

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: Thank you for allowing me to review this manuscript entitled “Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled Trials”

I have read with interest the article, which is overall well written, and I believe the findings are clinically significant. The methodology appears to be mostly sound and the conclusions are supported by the data.

A few comments:

I suggest providing funnel plots for all outcomes and performing a visual inspection, as this can be useful to interpret the results of Egger’s test, which is also not recommended in the Cochrane handbook when there are less than 10 studies (I suggest the relevant chapter in the cochrane handbook: https://training.cochrane.org/handbook/archive/v6/chapter-13).

I suggest adding to the limits that the subgroup analysis for the type of surgery, dose and species of probiotics/synbiotics was not possible due to the limited number of studies, as mentioned in the answer to Reviewer 1.

Aside from these aspects which in my opinion could benefit from clarification, I believe the manuscript is overall sound and interesting to read. I congratulate the authors for their interesting research.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

21 Feb 2022

PONE-D-21-20250R1

Prophylactic Effects of Probiotics or Synbiotics on Postoperative Ileus After Gastrointestinal Cancer Surgery: A Meta-analysis of Randomized Controlled Trials

Dear Dr. Wei:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Laura Pasin

Academic Editor

PLOS ONE