Introduction
Preparing the patient for surgery is an essential element of surgical treatment. This comprehensive preparation, called prehabilitation, includes 4 basic components: nutrition, psychological and physiotherapeutic preparation, and eliminating addictions [1]. Nutritional preparation is currently not limited to improving nutritional status, but it also includes other important elements of supplementation, such as immunomodulating nutrition and optimising the condition of the gastrointestinal mucosa through trophic nutrition or the use of probiotics. These multidisciplinary recommendations for prehabilitation of surgical patients were presented recently by Banasiewicz et al. [2] in a consensus panel format. The experts raised some issues related to probiotic therapy in a question dedicated to modifying the intestinal microbiota but did not reach unanimity in formulating specific recommendations regarding it in prehabilitation. Ultimately, it was suggested that this topic should be presented in a separate publication [2].
Perturbations in the gut microbiota (commonly referred to as dysbiosis) are caused by inappropriate changes in diet [3], use of antibiotics [4] and other medications [5], stress, and surgery and can lead to increased susceptibility to infection and inflammation [6]. Additionally, the importance of the microbiome in the development of surgical site infections (SSIs) is highlighted by the results of the study by Long et al. [7], which showed that 86% of SSIs in patients following spinal surgery, covering a wide range of bacterial species, originated from endogenous strains. In addition, most bacteria responsible for SSIs (59%) were resistant to prophylactic antibiotics, and their resistance phenotypes correlated with the patient’s preoperative resistance (p = 0.0002). These findings highlight the need for SSI prevention strategies tailored to the preoperative microbiome and resistome of individual patients. These observations challenge the common practice that a “one-size-fits-all” antibiotic regimen based on consensus guidelines and pre-selected information based on bacterial culture methods is “the best we can do” [8].
Optimisation of the gut microbiome is classified as individualised prehabilitation, i.e. specific proceedings related to the type of surgery and the clinical characteristics of the patients. Microbiome dysfunction is associated with impaired gastrointestinal peristalsis and impaired digestive function. Adequate preparation of the gut microbiota by administering pre- and probiotics may have a beneficial effect on reducing the risk associated with surgical treatment [9]. Probiotics and synbiotics play a key role in maintaining intestinal homeostasis by strengthening the intestinal barrier, modulating immune responses, and potentially reducing inflammation [10–13]. Products used to modify the intestinal microbiota are defined as follows: 1) prebiotics – food ingredients that cause specific changes in the composition and/or activity of the intestinal microbiota; 2) probiotics – live microorganisms that, when administered in appropriate amounts, have a beneficial effect on the health of the host; 3) synbiotics – composed of prebiotics and probiotics; and 4) postbiotics – non-living microorganisms and/or their components [14].
Modulating the patient’s microbiome to prevent the development of pathogens under the influence of antibiotic therapy and surgery could prove to be a rational solution [15].
The aim of this scoping review is to present the current knowledge on the use of pro-/synbiotics and postbiotics in prehabilitation, based on systematic reviews, meta-analyses, and randomised clinical trials (RCTs) with special emphasis on studies conducted in the Polish population and aspects related to the safety of such procedures.
Methods
The main phases of preparing this scoping review were as follows: (1) Formulating the research question: “What is the role of microbiota modifications with pro-, syn-, and postbiotics in prehabilitation?” A broad question was chosen to encompass as many facets of the topic as possible. (2) Identifying relevant studies: a search was conducted in PubMed using the following search terms: (‘probiotics’ OR ‘prebiotics’ OR ‘synbiotics’, OR ‘postbiotics’) AND (‘prehabilitation’ OR ‘surgery’). Systematic reviews, metanalyses, and some important RCTs were include in this study. Additionally, references from relevant reviews discussing the overall impact of microbiota modifications on surgery-related outcomes were manually reviewed. Issues related to metabolic disorders and safety were briefly described based on the current literature. Studies in English language were included without publication date restrictions but available by 12 April 2024. (3) Selecting studies: We included the systematic reviews, metanalyses, and some important RCTs involving humans. The first and senior authors carried out the selection process. (4) Data extraction. (5) Collating, summarising, and reporting the results.
Gut microbiota and surgery related complications
Impact of surgery on gut homeostasis and systemic inflammation
The gut microbiota consists of a diverse community of bacteria, fungi, archaea, protozoa, and viruses that symbiotically inhabit the human gastrointestinal tract and interact with the host through various mechanisms [16]. Changes in the microbiota can be associated with motoric (peristalsis), functional (absorption, production of vitamins and short-chain fatty acids (SCFAs), permeability of the intestinal barrier) and immunological (inflammatory responses, infections, impact on cancer development, metabolic complications) disturbances of the digestive tract. Surgery is stressful for both physical and psychological reasons. As a result, corticotropin activity may increase intestinal epithelial permeability and activate systemic inflammatory responses [17]. Surgery can also impact the composition of intestinal bacteria by its exposure to oxygen and its ischaemia. A specific example of surgery affecting the composition of the gut microbiota is bariatric surgery, which leads to functional deficiencies in the absorption of vitamins (e.g. B12) [18].
Postoperative bowel obstruction is a typical complication after abdominal surgery and is associated with several mechanisms including inflammation, inhibitory neural reflexes, and neurohormonal peptides [17]. Through these pathways, gut bacteria can influence gastrointestinal motility [19]. Agnes et al. also report that SSIs are common post-operative complications, in which E. coli, P. aeruginosa, and Enterococcus spp. play a major role [17]. Therefore, it has been suggested that modulation of the gut microbiota may have a beneficial effect on the prevention of these post-operative complications. Another major surgical complication, namely surgical site and deep organ infection, is thought to be related to anastomotic leakage (AL) after colorectal surgery. In their narrative review, Agnes et al. [17] stated that the intestinal microbiota promotes anastomotic healing through several pathophysiological mechanisms. They also report that AL is associated with low bacterial diversity, particularly the abundance of Bacteroidaceae and Lachnospiraceae. Finally, they concluded that the abundance of Enterobacteriaceae and the predominance of low bacterial diversity are correlated with an increased incidence of AL and therefore with many unfavourable postoperative outcomes.
The role of probiotics and synbiotics in surgical inflammation
Appropriate preparation of the intestinal microbiota through the administration of prebiotics and probiotics may have a beneficial effect on the composition and functions of the intestinal microbiota and result in fewer disturbances in the peri- and postoperative period [20]. Of particular interest is the use of microbiota modification to reduce the incidence of SSIs, infections affecting other organs and systems (e.g. pneumonia, urinary tract infections, Clostridioides difficile infection – CDI), AL, and metabolic disorders [15, 21]. Also of interest are the effects of these protocols on pain [22], gastrointestinal motility [23], and inflammatory responses [24], which influence the patient’s recovery after surgery.
There are numerous RCTs and meta-analyses suggesting a potentially beneficial effect of probiotics and/or synbiotics on postoperative patient outcomes. Most of the studies are in patients who have undergone colectomy for cancer [25–29]. Other studies have looked at patients with hepatobiliary cancer [30] and pancreatic cancer [31], and patients undergoing liver transplantation [32, 33]. Therefore, there is increasing evidence that the use of probiotics may be associated with a reduction in the incidence of infections and other complications associated with surgery.
The interventions analysed were heterogeneous and included probiotics, synbiotics, and fibre, as well as different timing strategies: intervention before, after, or both before and after surgery. The potential mechanisms of action of synbiotics were also analysed, including effects on the composition of the gut microbiota and inflammatory markers [9, 24]. Systematic reviews and meta-analyses of the results of these studies clearly indicate the benefits of microbiota modification, particularly in reducing infectious complications [15, 34–36].
Infectious complications
Kasatpibal et al. [37], in a network meta-analysis including 31 articles and a total of 2952 patients, found that the administration of synbiotics reduced the incidence of SSIs (relative risk (RR) 0.28, 95% confidence interval (CI): 0.12–0.64); pneumonia (RR = 0.28, 95% CI: 0.09–0.90); and sepsis (RR = 0.09, 95% CI: 0.01–0.94). It also shortened the length of hospital stay (weighted mean (WMD) = 9.66 days, 95% CI: 7.60–11.72) and the duration of antibiotic administration (WMD = 5.61 days, 95% CI: 3.19–8.02). There was no significant effect on mortality. In addition, they showed that the administration of synbiotics before and after surgery was more effective in reducing SSIs (RR = 0.23, 95% CI: 0.09–0.60) and urinary tract infections (RR = 0.48, 95% CI: 0.25–0.92). Postoperative administration of synbiotics was associated with a reduced incidence of pneumonia (RR = 0.14, 95% CI: 0.03–0.59) and several types of infections (RR = 0.33, 95% CI: 0.15–0.59). It was also found that pre- and postoperative synbiotic therapy was the most effective intervention in reducing the length of hospital stay (WMD = 9.82 days, 95% CI: 6.57–13.08). It was also associated with a shorter duration of antibiotic administration (WMD = 5.61 days, 95% CI: 2.72–8.50).
The next systematic review [34] that included only RCTs found a nearly 50% reduction in postoperative infectious complications in elective abdominal surgery with the perioperative use of pre-, pro-, and synbiotics (RR = 0.56, 95% CI: 0.46–0.69, p < 0.00001, n = 2723, I2 = 42%). It was found that synbiotics were more effective (RR = 0.46, 95% CI: 0.33–0.66, p < 0.0001, n = 1399, I2 = 53%) than probiotics (RR = 0.65, 95% CI: 0.53–0.80, p < 0.0001, n = 1324, I2 = 18%) in reducing post-operative infections. Furthermore, only the administration of synbiotics led to a reduction in total hospital stay, with a weighted mean difference of –3.89 days (95% CI: –6.60 to –1.18, p = 0.005, n = 535, I2 = 91%). No significant differences in mortality rates (RR = 0.98; 95% CI: from 0.54 to 1.80, p = 0.96, n = 1729, I2 = 0%) or in non-infectious complications were found [34].
Several other meta-analyses suggested that the use of synbiotics in patients hospitalised in intensive care units may have reduced the incidence of complications such as respiratory tract, urinary tract, and wound infections after gastrointestinal surgery, as well as the duration of hospital stay and antibiotic therapy, without a direct effect on mortality, and was more effective than their use only after surgery, significantly reducing the incidence of infections, hospital stay, and duration of antibiotic use [38–44].
In another meta-analysis included in this review, the authors evaluated 35 trials involving 3028 adult patients undergoing various surgical procedures; 16 trials involved the administration of probiotics and 19 involved synbiotics [15]. The results confirmed that pro- and synbiotics significantly reduced the incidence of surgical treatment complications (STCs), including abdominal distension, diarrhoea, pneumonia, sepsis, SSIs (including superficial ones), and urinary tract infections. They also confirmed a reduction in the duration of antibiotic use, post-operative fever, time to introduce fluids and solid foods, and overall length of hospital stay. These researchers further postulated that pro- and synbiotics helped to reduce SSIs and SRCs by modulating the intestinal immune response and increasing the production of SCFA. This hypothesis on the mechanism of action of microbiota modulation in surgical patients was supported by Chen et al., who showed that the use of probiotics effectively improves cellular and humoral immunity [45].
Chen et al. [46] performed a meta-analysis of 14 RCTs involving 1566 colorectal cancer patients (502 receiving probiotics, 273 receiving synbiotics, and 791 receiving placebo). They found that the use of probiotics or synbiotics significantly reduced the risk of postoperative infectious complications by 37% (RR = 0.63, 95% CI: 0.54–0.74, p < 0.001) in this group of patients. Furthermore, when considering 6 different types of postoperative infectious complications (sepsis, postoperative wound infection, central catheter-related infection, lung infection, urinary tract infection, and occurrence of diarrhoea), the use of probiotics or synbiotics was beneficial in reducing the incidence of each. The quality of the evidence was graded as follows: diarrhoea (high), sepsis (moderate), postoperative wound infection (moderate), lung infection (moderate), urinary tract infection (moderate), and central catheter-related infection (low). The authors emphasised that further research is needed to confirm these results, due to possible publication bias and variable quality of evidence [46].
Kinross et al. [36] found a lower incidence of postoperative sepsis and lower postoperative antibiotic use duration, especially with the perioperative use of synbiotics in patients undergoing elective general surgical procedures. A study by Zeng et al. [47] showed similar results in terms of postoperative infections, while reductions in markers of inflammation, gut dysbiosis, and non-infectious complications were also observed.
When looking at specific surgical procedures and the effects of probiotics on postoperative infections, similar results were found. In a study by Tang et al. in patients undergoing pancreaticoduodenectomy (Whipple), probiotic administration reduced the incidence of postoperative infection, gastric emptying time, duration of antibiotic therapy, and length of hospital stay without affecting mortality [31]. The beneficial effect of probiotics in reducing postoperative infections has also been demonstrated in patients undergoing liver transplantation. A meta-analysis of 4 trials involving 246 participants showed that transplant patients who received probiotics had a lower rate of post-operative infection (infection rate 7% vs. 35%), with a shorter duration of antibiotic treatment and fewer days of hospitalisation, both in the intensive care unit and in the hospital [33]. Similar results in liver transplant patients were found in a recent meta-analysis by Xu et al. [48].
The meta-analysis by Veziant et al. [26] included RCTs comparing perioperative administration of pro-/synbiotics with placebo or standard care in elective colorectal surgery. In total, 21 trials were included in this analysis, 15 of which tested probiotics and 6 of which tested synbiotics. There was a significant reduction in infectious complications (RR = 0.59, 95% CI: 0.47–0.75, I2 = 15%) and SSIs (RR = 0.70, 95% CI: 0.52–0.95, I2 0%). There was also a significant reduction in pulmonary (RR = 0.35, 95% CI: 0.20-0.63) and urinary (RR = 0.41, 95% CI: 0.19–0.87) infections, but not in AL (RR = 0.83, 95% CI: 0.47–1.48) or wound infections (RR = 0.74, 95% CI: 0.53–1.03). Sensitivity analysis showed no significant differences between probiotics and synbiotics in reducing postoperative infections. The results of this study suggest that probiotics/synbiotics are effective in reducing infectious complications after colorectal surgery, with a more pronounced effect in preventing pulmonary and urinary tract infections. The authors emphasised that more research is needed on the formulations and duration of use of probiotics or synbiotics before they can be definitively included in programmes to improve regeneration after elective colorectal surgery [26].
A meta-analysis of surgery associated with colorectal cancer published in 2024 by Chen et al. [49] included 10 studies in which probiotics were administered for 3 to 28 days, mainly in the perioperative period. Single- and multi-strain probiotics containing different species of Lactobacillus and Bifidobacterium were used at doses of 107–1014 CFU/g. Probiotic administration not only significantly reduced the incidence of SSIs (odds ratio (OR) = 0.45, 95% CI: 0.28–0.72, p < 0.001, I2 = 0.0%), but also shortened the length of hospital stay (WMD = –1.29 days, 95% CI: –2.27 to –0.32 days, p < 0.001, I2 = 22%). Moreover, subgroup analysis showed that interventions using multi-strain probiotics were more effective than those using single-strain probiotics [49].
In another meta-analysis, Jiang and Ren [50] assessed the effect of pro-/synbiotics on postoperative complications in patients undergoing colorectal surgery. Twelve trials involving 1567 patients were analysed. Probiotics/synbiotics significantly reduced the total number of infections (OR = 0.44, 95% CI: 0.35–0.56, p < 0.00001), SSIs (OR = 0.61, 95% CI: 0.45–0.81, p = 0.002), pneumonia (OR = 0.43, 95% CI: 0.25–0.72, p = 0.001), urinary tract infections (OR = 0.28, 95% CI: 0.14–0.56, p = 0.0003), but did not reduce postoperative AL (OR = 0.84, 95% CI: 0.50–1.41, p = 0.51).
A meta-analysis looking at abdominal surgery including 20 trials involving 1374 patients showed that patients in the probiotic/synbiotic group were 37% less likely to develop an SSI than those in the placebo or standard care groups (RR = 0.63, 95% CI: 0.41–0.98, N = 15 trials) [51]. Additionally, according to Liu et al., only multi-strain probiotics had a positive effect on the incidence of infections (OR = 0.30, 95% CI: 0.15–0.61, p = 0.0009), including both surgical site (OR = 0.48, 95% CI: 0.25–0.89, p = 0.02) and non-surgical site (OR = 0.36, 95% CI: 0.23–0.56, p < 0.00001) [52]. A lower incidence of SSIs (22.7% vs. 36.0%, p = 0.05) was also found in a post-hoc analysis of critically ill patients with multi-organ injury who took a set of 4 probiotics [53].
It is thought that the most important gut-brain-cutaneous mediator is the hypothalamic hormone oxytocin, the levels of which increase after probiotic supplementation. It plays a key role in wound healing and reparative capacity, and therefore probiotic supplementation may prove beneficial in reducing SSIs and wound healing time [54]. In fact, as shown in animal studies, probiotics can improve vascularisation and epithelialisation, reduce microbial burden, and inhibit biofilm formation, all of which have a beneficial effect on wound healing [55].
Ventilator-associated pneumonia
There are conflicting results regarding the beneficial effects of probiotics on ventilator-associated pneumonia (VAP) in critically ill, mechanically ventilated ICU patients. A study by Zeng et al. showed that probiotics may prevent VAP [56]. The results of the Cochrane meta-analysis showed that the use of probiotics reduces the incidence of VAP, but no clear conclusions can be drawn due to the heterogeneity of the studies regarding the dose and type of probiotics and the small number of study participants [57]. However, another prospective double-blind randomised study showed that critically ill patients who received probiotics had shorter ICU and hospital stays but a similar incidence of VAP [58]. The beneficial effect of probiotics on lung infections may be related to the influence of the gut microbiota on the gut-pulmonary axis [59].
Probiotics and antibiotics
Antibiotics given along with probiotics are more effective than antibiotics alone in preventing postoperative infections and other complications after colorectal surgery (meta-analysis of 14 trials with 1524 participants) [60]. The use of probiotics is also recommended during antibiotic therapy to prevent infections in patients undergoing organ transplantation [60]. Dudzicz et al. [61], in a retrospective study, observed a significant decrease in the incidence of CDI (from 44.9 to 7.2 per 1000 hospitalised patients, p = 0.005) after the introduction of the Lactiplantibacillus plantarum 299v strain as CDI prophylaxis in patients undergoing immunosuppression and antibiotic therapy, and a significant increase in the incidence of CDI (from 7.2 to 34.0 per 1000 hospitalised patients, p = 0.025) after discontinuing this method of prevention [61].
Probiotics in liver transplantation
Grąt et al. [62] tested the efficacy of probiotics in preventing infections (including CDI) in 55 patients in the early postoperative period after liver transplantation. Patients who received a probiotic preparation containing Bifidobacterium bifidum Rosell – 71, Lactobacillus helveticus Rosell – 52, Lacticaseibacillus casei Rosell – 215 and Lactococcus lactis Rosell – 1058 in this early period after successful liver transplantation had a significantly lower incidence of infections than patients who received a placebo (30-day infection rates: 4.8% vs. 34.8%, p = 0.02; 90-day infection rates: 4.8% vs. 47.8%, p = 0.002). In addition, a faster improvement in biochemical parameters of transplanted liver function was observed in patients receiving probiotics, namely lower plasma bilirubin concentration and a faster decrease in plasma aspartate and alanine aminotransferase activity (p = 0.02, p = 0.03, and p = 0.03, respectively). In a prospective, randomised, placebo-controlled trial, Rayes et al. [63] investigated the incidence of postoperative infections in 95 patients after liver transplantation. Patients were divided into 3 groups that differed in their method of early enteral nutrition. Patients who received prophylactic antibacterial treatment as part of selective bowel decontamination (SBD) had significantly more infections than those who received L. plantarum 299v and oat fibre. The incidence of infection in the placebo group (heat-inactivated L. plantarum 299v and oat fibre) was also lower than in the SBD patients [63].
Additionally, the meta-analysis conducted by Wibawa et al. demonstrated that probiotics were more effective than placebo or no treatment in reversing minimal hepatic encephalopathy (MHE) and lowering serum ammonia levels in MHE patients. However, probiotics were not found to be more effective than lactulose or L-ornithine L-aspartate (LOLA) in achieving these outcomes [64].
Anastomotic leakage
Although the microbiota plays an important role in the pathogenesis of AL, the results of studies on the use of prebiotics and probiotics in the prevention of this complication are unclear. The COLON study [65] investigated the relationship between dietary fibre intake and the risk of complications after colorectal cancer surgery in 1399 patients. Of the 1237 patients who underwent anastomosis, 5% experienced AL. Interestingly, higher fibre intake was associated with a lower risk of any complication, including cardiopulmonary complications, SSIs, or postoperative bowel obstruction, but no association with AL was found [65]. In a randomised, double-blind, placebo-controlled trial by Kotzampassi et al. [53], patients undergoing colorectal surgery received placebo or a probiotic preparation containing 4 strains of bacteria 1 day before surgery and continued treatment for 15 days after surgery. Of the 84 patients in the probiotic group, 1.2% developed AL, compared with 8.8% of the 80 patients in the placebo group. These results were statistically significant, and the trial was stopped early due to the high efficacy of the treatment. In the Veziant et al. [26] study described earlier, the data collected showed fewer infectious complications, but no differences were observed in AL. The evaluated studies differed in the timing of synbiotic/probiotic administration, the preparations used, and the doses, suggesting a need for further structured research in this area.
Postoperative pain
It is possible that probiotics may help reduce postoperative pain [22]. Rousseaux et al. found that oral administration of Lactobacillus spp. probiotics in the perioperative period may increase the patient’s pain threshold by interfering with opioid and cannabinoid receptors on intestinal epithelial cells in a manner similar to morphine [66]. In addition to a potential reduction in infectious and non-infectious complications, patients receiving probiotics also reported an improved quality of life [29, 67, 68].
Inflammatory bowel disease
A case can be made to advise the use of probiotics in the preoperative period in patients with non-specific inflammatory bowel diseases (IBDs). In the preparation of a patient with IBD, a special role is played by the preparation of the digestive tract before surgery, which is not only the organ to be operated on, but also the cause of the patient’s discomfort and symptoms [69]. Changes in the composition and functions of the gut microbiota are an increasingly emphasised element in the pathogenesis of IBDs. These changes determine the severity of inflammatory processes and epithelial destruction, which in turn negatively affect the gut microbiome further. Optimising the gut microbiome may be beneficial in patients with inflammatory bowel disease. The rationale for the use of probiotics in the treatment of inflammatory diseases is their anti-inflammatory properties (i.e. lowering calprotectin levels), their role in modulating the composition of the intestinal microbiota (i.e. restoring beneficial Lactobacillus and Bifidobacterium strains), the production of SCFA, and strengthening the integrity of the intestinal barrier. Studies on the effects of probiotics in patients with IBDs show high efficacy in patients with ulcerative colitis and pouchitis [70]. Particularly beneficial effects were observed when using a probiotic prepared according to the De Simone formula, which contains 8 strains of freeze-dried live bacterial cultures: Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactiplantibacillus plantarum, Lacticaseibacillus paracasei, and Lactobacillus delbrueckii subsp . bulgaricus. In addition to the direct normalisation of the microbiota, this probiotic formulation has a proven ability to stimulate healing processes in the gastrointestinal mucosa, which has been confirmed in patients with peptic ulcers [71].
It should be noted that the efficacy of probiotic treatment, and therefore the recommendation on use, varies considerably among the different IBDs. The ESPEN (European Society for Clinical Nutrition and Metabolism) guidelines recommend the use of probiotics in ulcerative colitis and pouchitis, whereas their use is not recommended in Crohn’s disease [72].
Pancreatic surgery
The incidence of pancreatic ductal adenocarcinoma (PDAC) has risen in recent decades, now ranking as the fourth leading cause of cancer-related deaths in the Western world [73]. Despite significant advances in surgery and perioperative treatments like chemotherapy, the prognosis for PDAC remains poor. Surgical resection is a key part of the multimodal treatment for pancreatic head malignancies, but even in top centres, it carries significant risks of perioperative complications, including morbidity and mortality [74]. Pancreatic surgery is often associated with surgical site infections (SSIs) and the development of postoperative pancreatic fistula (POPF). Recent research has identified a link between bacteriobilia and the occurrence of SSIs [75, 76]. Recent retrospective studies indicate that distinct microbiota may play a role in perioperative complications and mortality following pancreatic head resections. Stein-Thoeringer et al. revealed that the presence of Enterococcus spp. in the bile ducts of PDAC patients undergoing surgery is a significant risk factor for perioperative infections and increased postoperative and long-term mortality [77]. A recent meta-analysis [31] including 6 randomised controlled trials (RCTs) involving 294 participants who underwent pancreaticoduodenectomy found that probiotic or synbiotic supplementation did not significantly reduce perioperative mortality (RR = 0.34, 95% CI: 0.11–1.03), but it did lower the rates of postoperative infections (RR = 0.49, 95% CI: 0.34–0.70) and delayed gastric emptying (RR = 0.27, 95% CI: 0.09–0.76). It also reduced the length of hospital stays (MD = –7.87, 95% CI: –13.74 to –1.99) and the duration of antibiotic use (MD) = –6.75, 95% CI: –9.58 to –3.92) compared to the control group. Overall, probiotics or synbiotics can help prevent infections, reduce delayed gastric emptying, and shorten hospital stays and antibiotic use for patients undergoing pancreaticoduodenectomy. The exact mechanisms behind this are still not fully understood and require further research. However, it is believed that the benefits may involve supporting a healthier gut microbiome and minimising the translocation of harmful bacteria [34, 78]. A significant safety concern is the occurrence of reported cases of Lactobacillus sepsis [79] and bowel ischaemia in patients with acute pancreatitis. In one study, however, a new type of probiotic was administered directly into the small intestine of patients at high risk for poor bowel perfusion [80]; moreover, the study raises several important methodological concerns [81, 82], which raises questions about the broader applicability of these findings. In conclusion, the use of probiotics in prehabilitation during pancreatic surgery is promising; however, it requires further studies to evaluate the efficacy and safety of such procedure.
Probiotics/synbiotics – proposed modes of action
Intestinal barrier integrity
The use of probiotics affects the integrity of the intestinal barrier, as shown by occludin expression and a reduced lactulose to mannitol (L/M) absorption ratio [83, 84]. In an RCT studying colorectal cancer patients, probiotics were administered for 6 days before and 10 days after colectomy, resulting in a significantly lower L/M ratio the day before and 10 days after surgery. However, on the third postoperative day, L/M values were similar in both groups [85]. It was shown that probiotics increase transmembrane resistance and decrease permeability to horseradish peroxidase, suggesting a protective effect on the colonic epithelium [85, 86]. Zonulin, a marker of intestinal permeability, was decreased after surgery in the probiotic group, suggesting barrier protection [85, 87]. The beneficial effect of pro-/synbiotics is also confirmed by increased SCFA levels after surgery, suggesting further protection of the intestinal barrier [30, 88–91]. However, some RCTs showed no significant difference in intestinal permeability after the use of probiotics or synbiotics [92]. sIgA production supported by the use of pro-/synbiotics may reduce inflammation after surgery [93].
Intestinal motility
Perioperative administration of probiotics has a beneficial effect on bowel motility after colorectal surgery. A recent meta-analysis of 21 RCTs involving 1776 patients with gastrointestinal cancer showed that, compared with controls, the administration of probiotics and synbiotics alone or in combination significantly reduced the incidence of abdominal distension (RR = 0.62) and the incidence of postoperative bowel obstruction (RR = 0.47). More specifically, participants who received probiotics and synbiotics had shorter first flatus (mean difference (MD) = –0.53 days), shorter first defecation (MD = –0.78 days), shorter time to first solid food (MD = –0.25 days), shorter first fluid intake (MD = –0.29 days), and shorter hospital stay after surgery (MD = –1.43 days) [94].
Data from meta-analyses [25, 29, 95, 96] involving large numbers of participants have provided evidence that probiotic administration significantly reduces the incidence of antibiotic-related diarrhoea in surgical and non-surgical patients. This favourable result appears to be related to the type, dose, and different combinations of strains administered [95].
Inflammation
Perioperative use of pro-/synbiotics may attenuate systemic inflammatory responses, resulting in a more rapid reduction in levels of inflammatory markers such as C-reactive protein (CRP) and IL-6 and an increase in NK cell activity [15, 97]. Studies have shown that preoperative probiotics reduce IL-6 and CRP levels [93, 98], with similar effects observed with synbiotics [53]. However, some RCTs showed no statistically significant difference in postoperative levels of these markers [90–92, 99–103]. In the context of oncology and bariatric surgery, some studies suggest a beneficial effect of pro-/synbiotics, e.g. a significant reduction in IL-6 levels after surgery [30, 89]. However, other studies do not confirm these effects and show no significant difference in postoperative inflammation levels [104, 105]. In addition to inflammatory biomarkers, immunoglobulin and endotoxin concentrations can be reduced by the administration of probiotics after surgery [87, 93]. Also, preoperative oral administration of glucose solution with probiotics in patients with colorectal cancer promoted the reconstruction of the intestinal microbiota and reduced inflammation [105, 106].
Based on the publications presented above, the authors have included in Table I selected strains whose administration can be recommended for the prevention of postoperative complications [107].
Table I
Selected probiotic strains used to prevent postoperative complications [107]
Metabolic disorders and cardiovascular diseases
Modification of the microbiota in patients with metabolic disorders (such as diabetes) undergoing surgery is another promising target group. The basic function of the gut microbiota is to participate in the digestion of fibre and other nutrients [108]. The microbiota contributes approximately 4–10% of our daily caloric value (i.e. 80–200 kcal/day) by digesting ingested food. Disturbances in the microbiota can have numerous consequences, including adversely affecting metabolism, the immune and endocrine systems, the body’s energy homeostasis, and lipid metabolism. They also disrupt the proper structure and function of the intestinal barrier, the damage to which can allow microorganisms or their fragments (e.g. lipopolysaccharides) to enter the body and cause chronic inflammation [109]. The effect of probiotics in preventing obesity is strain-specific. Several in vitro and in vivo studies have shown that probiotics, especially L. casei, L. rhamnosus, L. gasseri, L. plantarum, and Bifidobacterium, i.e. B. longum, B. breve, and B. animalis, reduce BMI and body fat [110, 111]. The gut microbiota play a key role in the development and progression of type 2 diabetes mellitus (T2DM). Probiotics can regulate the secretion of insulin and gut hormones. Glucagon-like peptide 1 and peptide YY can reduce fat deposition in liver cells by modulating L-cells [112, 113]. In addition, the therapeutic potential of probiotics in T2DM is based on improving intestinal barrier function, increasing insulin sensitivity, and reducing serum lipopolysaccharide levels and antioxidant effects [114]. A meta-analysis [115] including 26 trials and 1947 patients showed that probiotics had a beneficial effect on fasting glucose levels in adults with T2DM, and that their effect was greater in people with poor diabetes control and those not taking insulin. Moreover, the use of probiotics in the reduction of risk of cardiovascular disorders deserves particular attention [116]. The latest systematic reviews and meta-analyses clearly show that probiotic use improves many health parameters in patients at risk of cardiovascular disease (diabetes, dyslipidaemia, metabolic syndrome, hypercholesterolaemia, hypertension). These include reductions in systolic and diastolic blood pressure, cholesterol, triglycerides, glucose, HbA1c, serum LDL-C, and BMI [117]. Interestingly, probiotics also reduce BMI and waist circumference in healthy people, as well as serum cholesterol concentration in overweight and obese people up to a BMI of 40 kg/m2. Postbiotics – i.e. pasteurised Akkermansia muciniphila MucT bacteria – offer great hope for the treatment of obesity and other metabolic disorders [118, 119]. This line of inquiry began with the initial observations that the gut microbiota in obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease contained reduced levels of A. muciniphila in animals and humans [120]. In addition, A. muciniphila levels in overweight and obese individuals have been found to be positively correlated with better metabolic status and greater efficacy of caloric restriction in reducing body weight [121, 122]. The mechanism of action of A. muciniphila is overall well understood. This bacterium acts through Amuc_1100, P9 proteins and SCFA. These compounds act on gastrointestinal epithelial cells by increasing mucus secretion, activating the secretion of GLP-1 and GLP-2, stimulating the production of bioactive lipids from the endocannabinoid system, and modulating the immune response [120, 123]. In a proof-of-concept study [118], it was observed that the administration of pasteurised A. muciniphila MucT effectively prevented the natural deterioration of parameters related to the metabolic syndrome in overweight and obese patients who did not follow a diet or increase their physical activity. Compared to placebo, pasteurised A. muciniphila MucT improved insulin sensitivity, and reduced insulinaemia and total plasma cholesterol concentration. Slight reductions in body weight, fat mass, and hip circumference were also observed compared to baseline. Supplementation with A. muciniphila MucT significantly reduced concentrations of markers of liver dysfunction and inflammation. This agent has been approved for marketing as a new food, and its safety has been confirmed by the scientific opinion of the European Food Safety Authority (EFSA) [124].
Table II shows probiotic strains that reduce the risk of cardiovascular diseases.
Table II
Probiotic strains that reduce the risk of cardiovascular diseases [107]
Probiotic safety
The safety of probiotic use in humans must be established on the basis of sound scientific principles following regional policies and guidelines. Since 2007, the EFSA has maintained and updated a list of probiotic species that are considered safe for human consumption. To be considered for the list, probiotic formulations need to meet basic classifications and pass the Qualified Presumption of Safety (QPS) [125, 126] and Novel Food criteria [124]. These classifications are based on taxonomic identification and comprehensive scientific data on the safety of use of a given strain, including 1) genotypic and phenotypic identification, 2) detection of virulence-related genes using validated whole genome sequencing (WGS), and toxin production potential (potential production of toxins must be considered for novel foods in relation to potentially unfavourable metabolic properties), 3) animal toxicity testing may be required for novel foods, 4) antimicrobial resistance risk assessment is required for all; determination of intrinsic or acquired resistance and potential transferred antimicrobial resistance genes. Because the effect of probiotics is strain dependent, it seems that the safety of their use should also be determined for individual strains separately. For example, it is not recommended that Saccharomyces boulardii be used in patients with a central venous catheter, in critical condition, or with a significantly compromised immune system. Great caution is also advised when using this probiotic in patients with impaired intestinal barrier integrity, which is often seen in patients treated with chemotherapy or radiotherapy [127]. In general, although probiotics are well tolerated, caution should be exercised when using them in immunocompromised patients [128, 129]. Further research is recommended to determine the ideal treatment regimen and to evaluate outcomes in different populations [25, 27, 29, 67]. Great caution should be applied, and it is certainly necessary to assess the balance of benefits and harms, before the use of probiotics in patients with the following: 1) immunodeficiency; 2) a serious general condition, hospitalised in intensive care; and 3) a central venous catheter. It should also be remembered that yoghurts, pickles, and other foods containing strains of bacteria with undocumented health benefits are not considered probiotics. Unlike fermented foods, probiotic products must meet many quality, safety, and efficacy criteria. These requirements are particularly important when probiotics are used in sick persons.
Limitations
As with any scoping review there are some limitations. First, the search strategy utilised may have missed some publications from smaller journals as well as some smaller trials. Second, the included studies were quite heterogeneous, as the duration, dose, types, concentrations, and timing of administration (perioperative, preoperative, postoperative, or combined) of probiotics and/or synbiotics varied considerably. In addition, some of the retrieved studies had small sample sizes, which may have affected the reliability and validity of their results.
Conclusions
This and other papers [16] provide evidence for an association between the gut microbiota and the development of postoperative complications. Modification of the gut microbiota with pro-, syn-, and postbiotics should be an element of prehabilitation, i.e. comprehensive preparation of the patient for surgery. It has been shown to reduce the incidence of SSIs, infections affecting other organs and systems (e.g. pneumonia, urinary tract infections, CDI), and metabolic disturbances in patients before surgery. It may also have a beneficial effect on the development of AL, pain, gastrointestinal motility, and inflammatory responses that affect a patient’s recovery after surgery. Results of systematic reviews and meta-analyses do not clearly indicate therapeutic regimens, including specific preparations, their administration time, and specific doses. However, based on RCT, authors propose specific strains that can be used in prehabilitation, together with their dosage. When using probiotics in surgical patients, it is important to consider QPS status, novel foods, EFSA opinions, appropriate quality, opinions of scientific bodies, and clinical trial results to assess the balance of benefits and harms. The effect of probiotics is very broad, and many of the effects described can be very useful in patients who are candidates for surgical treatment, especially if they have gastrointestinal dysfunction or are being prepared for gastrointestinal surgery.
