Sepsis is a major problem for health care organizations around the world and continues to be a leading cause of morbidity and mortality, especially in postoperative patients.1,2 The frequency of sepsis is increasing despite advances in antibiotic therapy and the implementation of infection control policies.2–5 The limitations of infection control strategies, as well as the increasing global concern about antimicrobial resistance, has led to the demand for novel or alternative strategies to reduce the risk of infection in surgical patients.
Probiotics are defined by the World Health Organization6 as live microorganisms which confer beneficial effects to the host when given in sufficient quantities. They survive transit through the gastrointestinal tract with the majority of their activity being in the colon.7 Prebiotics are food ingredients, which escape digestion in the upper gastrointestinal tract to stimulate the growth or activity of selective bacterial genera in the colon.8 When prebiotics and probiotics are combined in a single preparation they are known as synbiotics.9 These nutritional adjuncts have emerged as potential treatments that could help reduce the incidence of postoperative infection.
Probiotics have been shown to be useful in the treatment of gastrointestinal infections; they are effective along with oral rehydration therapy in treating acute infectious diarrhea in children,10–13 traveller's diarrhea,14 and antibiotic-associated diarrhea in both children15–17 and adults.18–21 Mechanisms of action for probiotics include competitive exclusion of potentially pathogenic bacteria and direct antimicrobial effects.22 Probiotics alter the pH of intestinal mucosa, produce bacteriocins which inhibit pathogenic epithelial adherence and production of virulence factor, and prevent bacterial translocation via tight junctions.22,23 Furthermore, probiotic bacteria have also been shown to promote anti-inflammatory cytokine production.22,24 The proliferation of probiotic bacteria can be enhanced by the co-administration of prebiotics; and certain bacterial genera are stimulated selectively by these compounds which supply nutrients for their growth.25
A number of randomized controlled trials (RCTs) have examined the value of prebiotics and probiotics in reducing postoperative complications with mixed results, most likely due to variations in methodological quality and endpoints. Serious adverse effects of probiotics are uncommon in those who are well, but it is theorized that these may occur in patients with impaired immunity. In patients with severe pancreatitis, administration of probiotics was associated with an increased frequency of bowel ischemia.26,27 This potential for adverse effects of probiotics warrants systematic review before their use in the perioperative setting can be recommended. This systematic review and meta-analysis of RCTs evaluated the effect of perioperative probiotics or synbiotics on postoperative infections in adult patients undergoing elective abdominal surgery.
The methodology for this meta-analysis was approved by the Cochrane Collaboration and the protocol was published in the Cochrane Library: Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD009246. DOI: 10.1002/14651858.CD009246. This strategy was amended since publication of the protocol to extend the search dates to 2018.
RCTs were identified from PubMed (1966–2018), Embase (1980–2018), and World Health Organization (WHO) Global Index Medicus. Search terms were used and connected by Boolean operators AND/OR and included Population: Adults Intervention: Probiotic, Probiotic, Synbiotics, Individual species/preparations. Disease condition: Abdominal Surgery, Operation, Laparotomy, Colorectal resection, Pancreatic Surgery, Infection, Sepsis, Collection, Abscess. References from relevant articles were scanned and primary authors consulted for additional information as necessary. Bibliographies of RCTs, meta-analyses, and systematic reviews were hand-searched for studies that were not captured by the initial search. Unpublished or ongoing studies were identified by checking clinical trials registers. The complete strategy for identifying RCTs is described in the Supplementary Document, Supplemental Digital Content, http://links.lww.com/SLA/B774.
Inclusion and Exclusion Criteria
Only RCTs evaluating perioperative probiotics or synbiotics in patients aged 18 years and older having elective abdominal surgery (including laparoscopic surgery) were included. Studies which included patients younger than 18 years of age or pregnant women were excluded.
The perioperative administration of probiotics or synbiotics given by any route, duration, combination or preparation was accepted. Control groups were defined as those that did not receive any probiotics or synbiotics and received either placebo or standard care.
The primary outcome was incidence of postoperative infectious complications as defined by the trial authors in each of the studies included, with a pre-planned subgroup analysis based on the type of preparations (probiotics and synbiotics). Secondary outcome measures included incidence of non-infectious postoperative complications, primary length of hospital stay (LOS), 30-day mortality, and any other reported adverse events. A further analysis based on the source of funding as reported in the individual studies, was undertaken to assess the role of this on outcome of studies.
Selection of Studies
The studies identified from the electronic searches were evaluated independently by 2 reviewers (A.H.C. and A.A.) using a study eligibility form based on the inclusion criteria. Titles and abstracts were initially screened for relevance. The full texts of potential studies were then retrieved, assessed independently and any discordance adjudicated by a third reviewer (D.N.L.).
Data Extraction and Management
Two reviewers (A.H.C. and .A.A.) extracted data independently from the full text publications of the RCTs that met the inclusion criteria using a standardized data extraction form and data were validated by a third reviewer (D.N.L.).
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement methodology28 was adhered to. Studies were appraised critically and the risk of bias of all included studies assessed according to the guidelines of The Cochrane Collaboration.29 Relative risk (RR) was reported along with 95% confidence intervals (CIs) to estimate treatment effects or discrete numerical variables. Weighted mean difference (WMD) was used for reporting continuous outcomes. Pooled data were analyzed using the random-effects model with the inverse variance or Mantel-Haenszel method as appropriate. As studies may have used different lengths of treatment, studies were subjected to metaregression to determine the most effective duration of treatment. Heterogeneity was quantified using the I2 statistic, with the values of 25%, 50%, and 75% signifying the limits of low, moderate, and high statistical heterogeneity, respectively.30 A funnel plot was used to explore publication bias for the studies included. All statistical analyses were performed using RevMan 5.3 software.31
The initial literature search identified 196 potential studies for inclusion in this analysis. Following application of exclusion criteria, 34 studies were deemed appropriate for full analysis (Fig. 1).
A large proportion of studies were excluded because they did not fulfill criteria for human RCTs, for example, they were not randomized, were performed as retrospective analyses, or were animal studies. Additional studies were excluded on the basis that they did not use probiotics, prebiotics, or synbiotics or were not undertaken in patients undergoing elective abdominal surgery. Eleven studies were excluded as they did not report infectious complications. An attempt to contact the authors (n = 8) was made for publications that qualified for analysis but did not contain the required information in the manuscript, but the responses were limited.
Of the 34 studies32–65 included in the final analysis, 16 used probiotics33,34,37,38,42–48,58,60,62,63,65 as the sole intervention with the remaining 18 studies using synbiotic preparations32,35,36,39–41,49–57,59,61,64 in comparison with placebos or standard care. All the studies identified were published after the year 2000. In total, 2723 participants were included in this analysis, of whom 1354 were randomized to receive either probiotic or synbiotic preparations, whereas 1369 received placebo or standard care.
Participants and Interventions
The mean (standard deviation) age of study participants receiving probiotics or synbiotics was 62.8 (11.4) and 62.4 (10.8) years for those receiving placebo or standard care. A variety of abdominal operations were included: elective colorectal, upper gastrointestinal, transplant, or hepatopancreaticobiliary surgery. Of the studies using probiotics alone, only 3 used a preparation containing a single probiotic species; Lactobacillus plantarum 299v46,47 or Bifidobacteria58 with the remainder using a mixture of probiotics. Similarly, of the studies using synbiotics, only 3 used preparations containing a single probiotic species.52,54,61 One study compared the use of either synbiotics or prebiotics with heat-deactivated probiotics to standard care.39 There were insufficient data to include prebiotics alone as a separate subgroup in this meta-analysis. An overview of the studies included32–65 and their design is summarized in Table 1 .
Tolerance and Side Effects of Interventions
There were no serious complications or deaths directly related to the intake of either probiotics or synbiotics. On the whole, intake was well tolerated, and rates of abdominal distension, cramps, and diarrhea were not significantly elevated compared to the placebo or standard care group. Adverse effects are summarized in Table 2.
Postoperative Infectious Complications
Data on postoperative infectious complications were reported in all 34 studies.32–65 Quantitative pooling of data showed a significant reduction in the incidence of postoperative infectious complications in the intervention group (Fig. 2). The risk of developing a postoperative infectious complication was almost halved (RR 0.56; 95% CI 0.46–0.69; P < 0.00001, I2 = 42%).
In subgroup analysis, there was significant reduction in the incidence of postoperative infectious complications when both intervention types were considered separately. However, the reduction in infectious complications was greater in participants receiving synbiotics (RR: 0.46; 95% CI: 0.33–0.66; P < 0.0001, I2 = 53%) than in those receiving probiotics alone (RR: 0.65; 95% CI: 0.53–0.80; P < 0.0001, I2 = 18%).
Duration of Treatment
Studies were subjected to a weighted linear multiple regression to determine the influence of treatment duration on incidence of postoperative infectious complications. The results of this weighted analysis demonstrated that although there was a trend for a reduction in postoperative infectious complications with increasing treatment duration, this relationship, was not statistically significant (r2 = 0.0047, P = 0.4554).
Length of Hospital Stay
A total of 12 studies40,43,44,51,52,54–57,59,61,63 reported on the outcome of length of primary hospital stay. Analysis of pooled data revealed a statistically significant difference between treatment groups (WMD: −2.59; 95% CI: −4.31 to −0.87, P = 0.003, I2 = 88%) (Fig. 3A). However, in subgroup analysis, the decrease in length of stay was only significant in the synbiotics group (WMD: −3.89; 95% CI: −6.60 to −1.18; P = 0.005, I2 = 91%) and not significant in the small probiotics only group (WMD: −0.65, CI: −2.03–0.72, P = 0.35, I2 = 65%).
A total of 23 studies32,33,35,37,39–41,43,44,46–50,53,55–57,59–62,64 reported data on mortality. Twelve studies33,37,39–41,43,44,49,53,56,61,62 recorded no deaths in either treatment arm. There was no significant difference in mortality between patients receiving probiotics or synbiotics compared with those who received placebo or standard care (RR: 0.98; 95% CI: 0.54–1.80; P = 0.96, I2 = 0%) (Fig. 3B) this was also confirmed on subgroups analysis.
Some studies provided a count of the number of participants with noninfectious complications; others reported the different types of complications but not the number of patients with these complications. In addition, what counted as noninfectious complications differed between individual studies, as such formal pooling of this outcome could not be undertaken. However, where number of patients with noninfectious complications were reported there was no significant difference between the treated and control arms in the individual studies.34,35,38,39,41,42,46,48–50,52,53,55–57,59–61,63–65
Impact of Source of Funding
We undertook a separate analysis to assess the impact corporate funding had on the primary outcome. Studies were stratified into “industry sponsored,” “undeclared,” and “not industry sponsored”—the RR favored probiotics/synbiotics in all cases [“industry sponsored” RR 0.65 (95% CI 0.53–0.81, P < 0.0001, I2 = 49%); “undeclared” RR 0.47 (95% CI 0.31–0.72, P = 0.0006, I2 = 52%) and “not industry sponsored” RR 0.25 (95% CI 0.09–0.69, P = 0.007, I2 = 17%).
It is recognized that studies are more likely to be published if positive outcomes are demonstrated. Consequently, published studies may not be truly representative of all valid studies undertaken. The assessment of publication bias based on the primary outcome of infectious complications showed minor asymmetry in favor of positive studies with fewer studies which cross the margin of no effect (Fig. 4).
Risk of Bias Analysis
The risk of bias of the studies included is summarized in Figure 5.
What This Study Found
The analysis of pooled data from RCTs demonstrates that the perioperative administration of probiotics and synbiotics significantly reduces the risk of infectious complications following abdominal surgery, with the magnitude of this risk reduction approaching 50%. The reduction in risk of infections was greater with synbiotic preparations than with probiotics alone, confirming that the beneficial effects of probiotics can be enhanced by the addition of prebiotic substrates. In addition, there was a reduction in LOS in the synbiotic group but not the probiotics group. There was no impact on noninfectious complications or mortality.
The studies included in this meta-analysis employed different treatment durations; the majority of the larger studies which provided most of weighting had treatment durations lasting more than 10 days. The reduction in infection risk remained whether treatment was given for less than 10 days or for 10 days or more. Separate weigthed metaregression of treatment duration against RR of infection did not reveal a significant relationship. This might be accounted for by 2 possible explanations, possibly that a minimum treatment duration is sufficient to observe an effect above which no additional effect is seen, or that the analysis lacks studies with a sufficient range of treatment durations thereby diminishing power. It is, therefore, difficult to infer either minimum or optimum duration of treatment from this analysis.
What is Available in the Literature
The reduction in infectious complications demonstrated in this meta-analysis are consistent with the results of other systematic reviews.66–69 In addition, Kinross et al67 also found a similarly pronounced benefit of synbiotics over probiotics. A reduction in postoperative infectious complications was also found in studies carried out in patients undergoing nonabdominal surgery.70
Importantly, both probiotics and synbiotics were tolerated well and were associated with few gastrointestinal adverse effects, even in participants who had undergone major gastrointestinal reconstructions or liver transplantation, where a significant degree of immunosuppression can occur. The serious complications of probiotic usage observed in nonsurgical patients such as bowel ischemia26 and Lactobacillus-related sepsis71 were not evident in the setting of elective abdominal surgery. It is noteworthy that the increased risk of bowel ischemia as detected in the PROPATRIA study26 has not been validated by a second study, thereby making the true clinical relevance of this association uncertain. Furthermore, a meta-analysis of 2972 critically ill patients admitted to the intensive care unit found no differences in rates of mortality between those who received probiotics and those who did not.72 Hence, the potential detrimental impact of probiotics in the acutely unwell patient has not been substantiated by this meta-analysis.72 The present meta-analysis also did not demonstrate any significant side effects of probiotics in the setting of elective abdominal surgery.
The studies varied in the types of patients and complexity of surgery carried out, ranging from elective colorectal resections for benign disease to complex hepatopancreaticobiliary resections and reconstructions for malignant disease. It would be expected that patients undergoing more complex surgery would be subject to a greater risk of complications and mortality and longer hospital stay. This was borne out in the data which showed that mortality was generally low in studies on colorectal surgery compared with hepatopancreaticobiliary surgery. On the whole, mortality rates were low, with the highest recorded for the study by Anderson et al32 with an overall mortality rate of 10.2%. This might be considered slightly high in the setting of elective abdominal surgery. Overall, there were, however, no significant differences in mortality demonstrated between patients who received probiotics or synbiotics (21 of 849 patients, 2.5%) compared with those receiving placebo or standard care (23 of 880 patients, 2.6%). The prior reviews also identified no differences in noninfectious complications or mortality.66–69
Perioperative administration of probiotics and synbiotics was seen to decrease length of stay significantly by 2 days in 12 studies that reported length of stay. There was, however, a high degree of statistical heterogeneity in the pooled synthesis. Length of stay is influenced by many confounding factors and not necessarily directly related to the incidence of infection. Length of stay data are also subject to bias if blinding of patients, healthcare staff, and study data analysts to treatment groups is not effective.
Although this meta-analysis does not provide any evidence for mechanism of action, it does indicate a role for the addition of prebiotic compounds to enhance the action of probiotics. Patients undergoing major abdominal surgery would be expected to experience a period of postoperative gut dysfunction which may have several important implications when administering probiotic or synbiotic preparations. For instance, delivery of probiotic bacteria to their proposed site of action may be impaired in the presence of vomiting or paralytic ileus. Any delay in the return to normal gut function may also disrupt local bacterial ecology and prevent the establishment of probiotic niches due to the impaired delivery of probiotic substrates during periods of inadequate enteral nutrition.
Although this meta-analysis has shown a clear reduction in the risk of infectious complications with probiotics and synbiotics, there was no significant effect on noninfectious complications, consistent with the proposed theory of the gut as an origin of sepsis and in agreement with the earlier reviews.66,67 Noninfectious complications are also likely to be influenced by confounding factors such as patient cohort, complexity of surgery, and access to critical care facilities. The analysis based on the source of funding demonstrated that the impact of probiotics and synbiotics on the primary outcome was preserved regardless of whether the studies were industry funded, undeclared, or unfunded.
It is difficult, from this analysis, to determine which probiotic or synbiotic strains were most effective in reducing infectious complications as the variability in species and genera used in the studies was wide. The majority of the studies used Lactobacilli either alone or in combinations with prebiotics. Twenty-one studies32,35,37,38,40–44,48–51,57–60,63–65 used Bifidobacteria species, whereas galacto-oligosaccharides, known to selectively enhance the growth of Bifidobacteria,73,74 were used in 6 of the studies.35,40,49,57,61,64 At present it is not certain whether some strains of probiotic bacteria are more effective at reducing infection risk than others. This, however, clearly remains an area for further study. In addition, 2 recent studies have suggested that the same probiotic supplement may behave differently in different individuals.75,76 Probiotics may not colonize the gut of all patients, suggesting that the bacteria may pass through the gastrointestinal tract of some people with no effect.76 The same group of investigators also showed that compared with spontaneous postantibiotic recovery, probiotics induced a delayed and incomplete return of the native microbiota and that potential postantibiotic benefits of probiotics may be offset by a compromised gut mucosal recovery.75 It has been proposed that in the not too distant future machine learning algorithms could be used to predict which particular strains of probiotics would be most beneficial on an individual patient basis.75–77 Although this is promising, it remains only a hypothesis at present.
Strengths and Limitations
This systematic review and meta-analysis comprehensively assessed clinically relevant outcomes in patients undergoing elective gastrointestinal surgery. It included searches of the major online databases as well as the WHO Global Index Medicus, allowing studies from low- and middle-income countries countries to also be identified. The focus on elective gastrointestinal surgery, helped reduce the within study and between study variability and heterogeneity.
There are however, a number of limitations to this analysis which warrant discussion. Firstly, there has been no standardization of preparation of probiotic, duration of treatment, or route of administration making comparison of the trials challenging. In addition, some studies have used synbiotics or multispecies preparations. Furthermore, control groups in some studies comprised only standard care, whereas other studies employed a placebo. This lack of consistency is likely to introduce significant heterogeneity and whilst we attempted to account for this by employing a random effects meta-analysis, this must be borne in mind when drawing any conclusions. Other sources of heterogeneity include the use of preoperative bowel preparation, pre- and postoperative antibiotic usage, and surgical technique, which were all, in general, reported poorly in all the studies. Large high-quality multicenter studies would be needed to reduce the influence of these factors.
Different probiotics and synbiotic preparations were used in the RCTs included, with some employing a singular strain and others a cocktail or combinations of strains (Table 1 ). As such subgroup analysis based on strain of probiotics used could not be achieved in any clinically meaningfully way due to the wide spread of strains used in the individual studies. More work is required in exact strain identification and characterization of strain-specific clinical effects. Although perioperative administration of probiotics and synbiotics used in the studies included in this meta-analysis demonstrated a reduction in infectious complications, all probiotic bacterial strains cannot be interpreted as equivalent. As such the clinically beneficial effects of a select number of bacterial strains cannot be simply extrapolated to other strain(s) of probiotics not yet subjected to a rigorous RCT. It must, therefore, be stressed that the findings of this meta-analysis are only applicable to the strains studied in the individual RCTs.
This would ensure future reviews could pursue analysis of benefit based on different probiotic strain preparations to potential identify which species of probiotics or synbiotics harbor the most clinical benefit.
Probiotics and synbiotics are safe in the setting of elective abdominal surgery and associated with few adverse effects. Both probiotics and synbiotics reduce the risk of postoperative infection but the effect is greater for synbiotics than for probiotics. Further large multicenter studies with standardization of probiotic and synbiotic preparations, participants, type of surgery, and postoperative care are required before the effectiveness of particular preparations and optimum duration of treatment can be established.
1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med
2. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med
3. Bateman BT, Schmidt U, Berman MF, et al. Temporal trends in the epidemiology of severe postoperative sepsis after elective surgery: a large, nationwide sample. Anesthesiology
4. Moore LJ, Moore FA, Todd SR, et al. Sepsis in general surgery: the 2005–2007 national surgical quality improvement program perspective. Arch Surg
5. Vogel TR, Dombrovskiy VY, Carson JL, et al. Postoperative sepsis in the United States. Ann Surg
6. WHO/FAO. Probiotics in Food: Health and Nutritional Properties and Guidelines for Evaluation. Rome: World Health Organization/Food and Agriculture Organization of the United Nations; 2006.
7. Rabot S, Rafter J, Rijkers GT, et al. Guidance for substantiating the evidence for beneficial effects of probiotics: impact of probiotics on digestive system metabolism. J Nutr
8. Roberfroid M, Gibson GR, Hoyles L, et al. Prebiotic effects: metabolic and health benefits. Br J Nutr
2010; 104: (suppl 2): S1–S63.
9. De Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics
. Adv Biochem Eng Biotechnol
10. Allen SJ, Martinez EG, Gregorio GV, et al. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev
11. Huang JS, Bousvaros A, Lee JW, et al. Efficacy of probiotic use in acute diarrhea in children: a meta-analysis. Dig Dis Sci
12. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr
2001; 33: (suppl 2): S17–S25.
13. Van Niel CW, Feudtner C, Garrison MM, et al. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics
14. McFarland LV. Meta-analysis of probiotics for the prevention of traveler's diarrhea. Travel Med Infect Dis
15. Johnston BC, Supina AL, Ospina M, et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev
16. Johnston BC, Supina AL, Vohra S. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials. CMAJ
17. Szajewska H, Ruszczynski M, Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials. J Pediatr
18. Cremonini F, Di Caro S, Nista EC, et al. Meta-analysis: the effect of probiotic administration on antibiotic-associated diarrhoea. Aliment Pharmacol Ther
19. D'Souza AL, Rajkumar C, Cooke J, et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ
20. Hawrelak JA, Whitten DL, Myers SP. Is Lactobacillus rhamnosus
GG effective in preventing the onset of antibiotic-associated diarrhoea: a systematic review. Digestion
21. Szajewska H, Mrukowicz J. Meta-analysis: non-pathogenic yeast Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther
22. Ng SC, Hart AL, Kamm MA, et al. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis
23. Morrow LE, Kollef MH. Probiotics in the intensive care unit: why controversies and confusion abound. Crit Care
24. Walker WA. Mechanisms of action of probiotics. Clin Infect Dis
2008; 46: (suppl 2): S87–S91. discussion S144–S151.
25. Roberfroid M. Prebiotics: the concept revisited. J Nutr
26. Besselink MG, Van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet
27. Expression of concern--probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet
28. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med
29. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Copenhagen: The Cochrane Collaboration; 2011.
30. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med
31. Review Manager (RevMan) [Computer program]. Version 5. 3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
32. Anderson AD, McNaught CE, Jain PK, et al. Randomised clinical trial of synbiotic therapy in elective surgical patients. Gut
33. Consoli ML, Da Silva RS, Nicoli JR, et al. Randomized clinical trial: impact of oral administration of Saccharomyces boulardii
on gene expression of intestinal cytokines in patients undergoing colon resection. JPEN J Parenter Enteral Nutr
34. Diepenhorst GM, Van Ruler O, Besselink MG, et al. Influence of prophylactic probiotics and selective decontamination on bacterial translocation in patients undergoing pancreatic surgery: a randomized controlled trial. Shock
35. Eguchi S, Takatsuki M, Hidaka M, et al. Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation: a prospective randomized study. Am J Surg
36. Flesch AT, Tonial ST, Contu PC, et al. Perioperative synbiotics
administration decreases postoperative infections in patients with colorectal cancer: a randomized, double-blind clinical trial. Rev Col Bras Cir
37. Gianotti L, Morelli L, Galbiati F, et al. A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J Gastroenterol
38. Grat M, Wronka KM, Lewandowski Z, et al. Effects of continuous use of probiotics before liver transplantation: a randomized, double-blind, placebo-controlled trial. Clin Nutr
39. Horvat M, Krebs B, Potrc S, et al. Preoperative synbiotic bowel conditioning for elective colorectal surgery. Wien Klin Wochenschr
2010; 122: (suppl 2): 26–30.
40. Kanazawa H, Nagino M, Kamiya S, et al. Synbiotics
reduce postoperative infectious complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy. Langenbecks Arch Surg
41. Komatsu S, Sakamoto E, Norimizu S, et al. Efficacy of perioperative synbiotics
treatment for the prevention of surgical site infection after laparoscopic colorectal surgery: a randomized controlled trial. Surg Today
42. Kotzampassi K, Stavrou G, Damoraki G, et al. A four-probiotics regimen reduces postoperative complications after colorectal surgery: a randomized, double-blind, placebo-controlled study. World J Surg
43. Liu Z, Li C, Huang M, et al. Positive regulatory effects of perioperative probiotic treatment on postoperative liver complications after colorectal liver metastases surgery: a double-center and double-blind randomized clinical trial. BMC Gastroenterol
44. Liu Z, Qin H, Yang Z, et al. Randomised clinical trial: the effects of perioperative probiotic treatment on barrier function and post-operative infectious complications in colorectal cancer surgery—a double-blind study. Aliment Pharmacol Ther
45. Liu ZH, Huang MJ, Zhang XW, et al. The effects of perioperative probiotic treatment on serum zonulin concentration and subsequent postoperative infectious complications after colorectal cancer surgery: a double-center and double-blind randomized clinical trial. Am J Clin Nutr
46. Mangell P, Thorlacius H, Syk I, et al. Lactobacillus plantarum
299v does not reduce enteric bacteria or bacterial translocation in patients undergoing colon resection. Dig Dis Sci
47. McNaught CE, Woodcock NP, MacFie J, et al. A prospective randomised study of the probiotic Lactobacillus plantarum
299 V on indices of gut barrier function in elective surgical patients. Gut
48. Nomura T, Tsuchiya Y, Nashimoto A, et al. Probiotics reduce infectious complications after pancreaticoduodenectomy. Hepatogastroenterology
49. Okazaki M, Matsukuma S, Suto R, et al. Perioperative synbiotic therapy in elderly patients undergoing gastroenterological surgery: a prospective, randomized control trial. Nutrition
50. Polakowski CB, Kato M, Preti VB, et al. Impact of the preoperative use of synbiotics
in colorectal cancer patients: a prospective, randomized, double-blind, placebo-controlled study. Nutrition
51. Rammohan A, Sathyanesan J, Rajendran K, et al. Synbiotics
in surgery for chronic pancreatitis: are they truly effective? A single-blind prospective randomized control trial. Ann Surg
52. Rayes N, Hansen S, Seehofer D, et al. Early enteral supply of fiber and Lactobacilli versus conventional nutrition: a controlled trial in patients with major abdominal surgery. Nutrition
53. Rayes N, Pilarski T, Stockmann M, et al. Effect of pre- and probiotics on liver regeneration after resection: a randomised, double-blind pilot study. Benef Microbes
54. Rayes N, Seehofer D, Hansen S, et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation
55. Rayes N, Seehofer D, Theruvath T, et al. Effect of enteral nutrition and synbiotics
on bacterial infection rates after pylorus-preserving pancreatoduodenectomy: a randomized, double-blind trial. Ann Surg
56. Rayes N, Seehofer D, Theruvath T, et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation—a randomized, double-blind trial. Am J Transplant
57. Russolillo N, Ferrero A, Vigano L, et al. Impact of perioperative symbiotic therapy on infectious morbidity after HPB Surgery in jaundiced patients: a randomized controlled trial. Updates Surg
58. Sadahiro S, Suzuki T, Tanaka A, et al. Comparison between oral antibiotics and probiotics as bowel preparation for elective colon cancer surgery to prevent infection: prospective randomized trial. Surgery
59. Sommacal HM, Bersch VP, Vitola SP, et al. Perioperative synbiotics
decrease postoperative complications in periampullary neoplasms: a randomized, double-blind clinical trial. Nutr Cancer
60. Tan CK, Said S, Rajandram R, et al. Pre-surgical administration of microbial cell preparation in colorectal cancer patients: a randomized controlled trial. World J Surg
61. Usami M, Miyoshi M, Kanbara Y, et al. Effects of perioperative synbiotic treatment on infectious complications, intestinal integrity, and fecal flora and organic acids in hepatic surgery with or without cirrhosis. JPEN J Parenter Enteral Nutr
62. Woodard GA, Encarnacion B, Downey JR, et al. Probiotics improve outcomes after Roux-en-Y gastric bypass surgery: a prospective randomized trial. J Gastrointest Surg
63. Yang Y, Xia Y, Chen H, et al. The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial. Oncotarget
64. Yokoyama Y, Miyake T, Kokuryo T, et al. Effect of perioperative synbiotic treatment on bacterial translocation and postoperative infectious complications after pancreatoduodenectomy. Dig Surg
65. Zhang JW, Du P, Gao J, et al. Preoperative probiotics decrease postoperative infectious complications of colorectal cancer. Am J Med Sci
66. Pitsouni E, Alexiou V, Saridakis V, et al. Does the use of probiotics/synbiotics
prevent postoperative infections in patients undergoing abdominal surgery? A meta-analysis of randomized controlled trials. Eur J Clin Pharmacol
67. Kinross JM, Markar S, Karthikesalingam A, et al. A meta-analysis of probiotic and synbiotic use in elective surgery: does nutrition modulation of the gut microbiome improve clinical outcome? JPEN J Parenter Enteral Nutr
68. Rayes N, Seehofer D, Neuhaus P. Prebiotics, probiotics, synbiotics
in surgery—are they only trendy, truly effective or even dangerous? Langenbecks Arch Surg
69. He D, Wang HY, Feng JY, et al. Use of pro-/synbiotics
as prophylaxis in patients undergoing colorectal resection for cancer: a meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol
70. Tanaka K, Yano M, Motoori M, et al. Impact of perioperative administration of synbiotics
in patients with esophageal cancer undergoing esophagectomy: a prospective randomized controlled trial. Surgery
71. Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr
72. Manzanares W, Lemieux M, Langlois PL, et al. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care
73. Garrido D, Ruiz-Moyano S, Jimenez-Espinoza R, et al. Utilization of galactooligosaccharides by Bifidobacterium longum
subsp. infantis isolates. Food Microbiol
74. Depeint F, Tzortzis G, Vulevic J, et al. Prebiotic evaluation of a novel galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum
NCIMB 41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study. Am J Clin Nutr
75. Suez J, Zmora N, Zilberman-Schapira G, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell
2018; 174:1406–1423. e1416.
76. Zmora N, Zilberman-Schapira G, Suez J, et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell
2018; 174: 1388-1405.e21.
77. Abbasi J. Are probiotics money down the toilet? Or worse? JAMA