Background
Every human being lives in a sensitive balance with an amount of different microorganisms [
1‐
4]. The constitutional symbiosis between the host and his microbiome suggests that there is a relationship regarding human health. A variety of diseases like Crohn’s disease and Ulcerative Colitis are nowadays known to be associated with the gut microbiome [
5,
6]. The microbiome is influenced by various factors like psychological stress, the circadian rhythm and cultural as well as ethnical factors [
2,
7]. Also eating habits affect the microbiome, especially the flora of the gut [
8,
9]. The technical progress of the last decades allows rapid and reliable gut microbiome analysis with next generation sequencing [
3]. Therefore, it was possible to get new insights into the microbiological spectrum of the gut. The flora of the gut is dominated by strains of Firmicutes and Bacteroidetes [
2,
3]. Potentially pathogenic bacteria like Pseudomonas, Enterobacteriacae like Escherichia and Klebsiella, Enterococcus and Staphylococcus also occur in the normal gut flora, but only in small quantities [
2,
6]. Recent literature suggests that these bacteria might be involved in development of infectious complications after gastrointestinal surgery [
2,
10,
11]. Infectious complications are a leading problem after gastrointestinal surgery and are associated with high mortality and morbidity rates [
12,
13]. Despite addressing the established risk factors for gastrointestinal surgical complications by e. g. improved operation techniques, the published rates of anastomotic leakage and wound infections remain a relevant problem and did not change in the past years. It strongly varies (3–30% for anastomotic leakage) between hospitals and patients groups and the cause of this variation is widely unknown [
12,
14]. The above-mentioned influence of the gut flora might be more important than previously expected. Recent reviews found a relationship between the development of an anastomotic leakage and the gut flora [
1,
15‐
17]. These reviews however focused on preclinical data and did not comprehensively consider the clinical evidence. Consequently, it is necessary to review the current literature from a clinical perspective. In respect to the advance of science this review summarizes the current literature and intends to highlight the relationship between the gut flora and the development of postoperative complications after surgical procedures on the gastrointestinal tract.
Discussion
Whether or not the gut microbiota are related to anastomotic leakage or wound infection after gastrointestinal surgery remains a highly relevant question with regard to the management of patients undergoing abdominal surgery. The results of the ten included studies suggest that there might be a relationship between the gut flora and the development of postoperative complications. The quality of the publications, however, is too low to draw firm conclusions. Every surgical procedure is a challenging situation for a human being and is associated with an inflammatory response, which depends on the surgical technique [
45,
46]. It is therefore problematic to compare the effects of different operation techniques. In addition, the different operation techniques may differently influence the gut microbiome, e.g. colorectal surgery might have a higher influence on the gut microbiome than operations, which do not directly involve the gut. Although the influence of operation related parameters on the postoperative course is known, most of the reviewed studies gave only little information on operation time and exact technique [
46].
The balance of the microbiome is susceptible for external factors like nutrition [
2]. A well-defined pre- and postoperative nutrition is, therefore, important for studies investigating the impact of surgery on the gut flora. Most of the studies classified the preoperative and postoperative nutrition as regular. None of the studies, however, defined what this meant exactly. In addition, most of the studies failed to give detailed information about an additional postoperative antibiotic treatment.
Another problematic aspect is the constitution of the gut flora. The importance of a healthy gut microbiome became popular in the last years, but it is not clarified what kind of microbiological spectrum is healthy and what is not. Stool samples of putatively healthy subjects showed a broad spectrum of gut microbiota [
3]. In the included studies the terms “harmful” and “beneficial” appeared to describe gut bacteria. For example Enterococci were often regarded as harmful, although it is known that Enterococci also have beneficial functions [
47]. Because the role of different bacteria in the gastrointestinal tract is widely unknown it is also unclear, which kind of bacteria is optimal for treatment. Most of the reviewed studies applied a combination of probiotic and synbiotic preparations (Lactobacillus casei, Bifidobacterium breve and Galactooligosaccharides) [
35,
37,
39‐
42]. The selection criteria for each combination are not reported.
Another unclear point is, whether changes of the microbiome are just an indicator for infectious complications or play a causal role. The reviewed studies used the term “infectious complication” not homogeneously and without a clear definition. Although e. g. a postoperative pneumonia could be rated as an infectious complication it is obviously not the same as a urinary tract infection or an anastomotic leakage. A few of the reviewed RCT summarized all of them and compared the results between control and treatment group. Some also added signs of systemic infection like SIRS or septicemia to the list of infectious complications. Such a method of summarizing is debatable and might blur the results.
Finally, this discussion turns to the examination of stool, which is a crucial point. The examination of stool by culture is not that meaningful, it is just a selection of the gut flora, not an evaluation of the whole bacterial diversity. In the last years PCR has been established to investigate the microflora. With this technique it has been shown, that the diversity of the flora is a deciding parameter [
1,
8]. However, for the analysis of sequencing results experience is needed. The method is sensitive and the samples could easily be contaminated [
48]. As a consequence of this only few laboratories have the ability for an advanced microbiome analysis. The analysis of the microbiome of the gut is still not a routine examination. This might be one more reason why the clinical evidence for a relation between gut flora and surgical complications is still not proven.
Despite a critical view on the reviewed studies is necessary and justified, the lower infection rate in patients, which were treated with probiotics or synbiotics, is promising. Eight of nine RCT showed a benefit with regards to infectious complications in patients, who were treated with synbiotics or probiotics. Only one of nine reviewed RCTs did not show the same effect on the gut flora and reported even a contrary effect [
40]. This study, however, was flawed by randomization bias. The patients in the intervention group had significantly longer operation time, significantly larger blood loss during operation and larger dimension of resection. All of these factors might influence the gut microbiome and might cause contrary results. Although patients treated with synbiotics had worse operation related conditions they still had an apparently better postoperative healing than patients of the control group. Therefore this study does not contradict the assumption of beneficial effects of synbiotics.
Moreover, the results of three double-blinded RCTs indicated that the application of synbiotics or probiotics improved the postoperative bowel function. Postoperative disturbances of the bowel function are a relevant problem for patients. They can cause abdominal distension, causing nausea, vomiting and abdominal pain, which may result in a delayed oral nutrition and mobilization [
49]. If modulation of the microflora could prevent these complications, it would be an improvement.
The probability of preventing postoperative complications like wound infections by modification of the gut flora, furthermore, is supported by an amount of clinical trials, which investigated the benefit of perioperative application of antibiotics. In colorectal surgery the application of antibiotics is thought to reduce the rate of postoperative wound infection by as much as 75% and is therefore a standard in colorectal surgery [
23]. To overcome the gap of knowledge we suggest a prospective cohort study without probiotics/synbiotics intervention but with strict control of possible bias/confounding factors comparing patients with and without postoperative complications in regards to the microbiome diversity measured with next generation sequencing.
Acknowledgments
Special thanks to K. Elisabeth Runte, M.D., Department of Pediatrics, University of Vermont, College of Medicine, Burlington, Vermont, USA for writing assistance.