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Ann Gastroenterol. 2017; 30(1): 45–53.
Published online 2016 Sep 6. doi: 10.20524/aog.2016.0086
PMCID: PMC5198246
PMID: 28042237
GUT MICROBIOME, SURGICAL COMPLICATIONS AND PROBIOTICS
George Stavrou and Katerina Kotzampassi
GEORGE STAVROU
Department of Surgery, Faculty of Medicine, Aristotle University of
Thessaloniki, Thessaloniki, Greece
Find articles by George Stavrou
KATERINA KOTZAMPASSI
Department of Surgery, Faculty of Medicine, Aristotle University of
Thessaloniki, Thessaloniki, Greece
Find articles by Katerina Kotzampassi
Author information Article notes Copyright and License information PMC
Disclaimer
Department of Surgery, Faculty of Medicine, Aristotle University of
Thessaloniki, Thessaloniki, Greece
Correspondence to: Katerina Kotzampassi, MD, PhD, Department of Surgery,
Aristotle University of Thessaloniki, Faculty of Medicine, Thessaloniki, Greece,
e-mail: moc.oohay@ehtokak
Received 2016 May 5; Accepted 2016 Jul 11.
Copyright : © Hellenic Society of Gastroenterology
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Go to:
ABSTRACT
The trigger for infectious complications in patients following major abdominal
operations is classically attributed to endogenous enteral bacterial
translocation, due to the critical condition of the gut. Today, extensive gut
microbiome analysis has enabled us to understand that almost all
“evidence-based” surgical or medical intervention (antibiotics, bowel
preparation, opioids, deprivation of nutrition), in addition to stress-released
hormones, could affect the relative abundance and diversity of the enteral
microbiome, allowing harmful bacteria to proliferate in the place of depressed
beneficial species. Furthermore, these bacteria, after tight sensing of host
stress and its consequent humoral alterations, can and do switch their virulence
accordingly, towards invasion of the host. Probiotics are the exogenously given,
beneficial clusters of live bacteria that, upon digestion, seem to succeed in
partially restoring the distorted microbial diversity, thus reducing the
infectious complications occurring in surgical and critically ill patients. This
review presents the latest data on the interrelationship between the gut
microbiome and the occurrence of complications after colon surgery, and the
efficacy of probiotics as therapeutic instruments for changing the bacterial
imbalance.
Keywords: Gut microbiome, surgical complications, colon surgery, colon
anastomosis, probiotics
Go to:
INTRODUCTION
Complications after colorectal surgery – especially those performed for
malignancy – are often a result of bacterial infections, leading to a
significant increase in morbidity and mortality, as well as the duration of
hospitalization and the subsequent costs. In this process, the gut seems to play
a crucial part. Failure of the gut barrier function has long been considered to
lead to a process called “bacterial translocation”, where whole bacteria or
their virulent products enter the systemic circulation and provoke systemic
inflammatory response syndrome (SIRS), which may lead to multiple organ failure
or even death. Human studies have shown that at least 11% of individuals who
undergo an open-abdomen surgical operation have experienced translocation of
live bacteria to the mesenteric lymph nodes or to the serosa of the bowel wall.
Evidence of bacterial DNA in the blood of approximately 50% of patients in the
intensive care unit (ICU) also suggests bacterial translocation, but there is
still a great deal of controversy as to whether this is only an epiphenomenon,
or whether it really contributes to morbidity [1,2].
In recent years, there has been ongoing interest in the human gut microbial
ecosystem, which ultimately appears to be involved in both disease onset and
progression, as well as in the development of complications. Moreover, there is
increasing recognition of the important fact that microbes can obtain
information from their host environment, which they then utilize to determine
whether to colonize or express a virulent phenotype to invade the host, a
scenario especially prevalent during prolonged critical illness [3-5].
In this review, efforts were made to present the newest data on the
interrelationship between gut microbiome and the emergence of complications
after colon surgery, and the efficacy of probiotics as therapeutic instruments
for changing the bacterial imbalance.
Go to:
INTESTINAL MICROBIOTA: SYMBIOSIS AND DYSBIOSIS
The gastrointestinal tract hosts a particularly complex microbial ecosystem,
consisting of more than 1014 microbes representing 500-1500 species. This
ecosystem remains relatively stable throughout life, leading to the speculation
that individuals might possess a unique microbial “fingerprint”, despite daily
variations attributable to diet, lifestyle, age, and the host’s physiological
and immunological health. All microorganisms residing within or on the human
body are called microbiota, and their genomes are known as the human microbiome
[6,7].
The four dominant phyla inhabitants of the human gut are Firmicutes and
Bacteroidetes, accounting for more than 90% of the bacteria cells, with a
smaller representation of Actinobacteria and Proteobacteria. Species from the
genus Bacteroides alone constitute about 30% of all bacteria in the human
microbiome, while the well-known family Enterobacteriaceae, which contains
medically relevant genera such as Escherichia, Klebsiella, Pseudomonas, and
Salmonella, actually represents less than 1% [4,8-11] (Fig. 1).
Open in a separate window
Figure 1
Distribution of the intestinal microbiota phyla
This complex ecosystem coexists in a fragile balance (symbiosis), that can
easily be disturbed (dysbiosis). This occurs when a disturbance in the
composition and function of beneficial bacteria makes them incapable of
controlling the harmful bacteria successfully. Today, dysbiosis has been linked
with important human diseases, not only infections, but also autoimmune and
autoinflammatory disorders, [8,12]. In this context, there is now clear evidence
that every direct or indirect manipulation of gut microbiota – by means, for
example, of antibiotics or surgery – contributes to disease development or the
opposite: a broad range of medical and surgical problems are linked to
perturbations of the microbiome (Table 1).
TABLE 1
Iatrogenic factors affecting the gut microbiome
Open in a separate window
INTESTINAL MICROBIOME AND COLON SURGERY
Intestinal microbiota and the human gut epithelium, serving as the host,
maintain a long-term, well-tolerated symbiotic relationship. When the host
“alters” the conditions of “hospitality”, as occurs with the physiologic changes
in the human body caused by surgical stress, and more specifically of the
intestinal microenvironment, a disturbance in ecological balance occurs [13].
However, the fact that most surgical patients do not experience infectious
complications simply underlines the adaptability of both the host and microbe in
response to surgical stress [1,4,14]. It is also recognized that, besides the
extent and severity of surgical stress, the variability of the inflammatory
response is also mediated by genetic predisposition, the presence of
comorbidities and the side-effects of pharmacologic treatments.
In a recent study in piglets, DNA sequencing of the colonic content was studied
comparatively in the “transection surgery” group and in the “no-surgery” group,
two weeks after operation. Changes in the relative abundance of bacterial
species were confined to Proteobacteria and Bacteroidetes phyla, while, at
family level, there was evidence of a reduction in Enterobacteriaceae,
Bacteroidaceae, and Rhodospirillaceae versus controls [15].
In colon surgery patients, there is not only the operative stress itself, but
also a variety of perioperative interventions imposed by modern intensive care
therapy, including preoperative bowel cleansing, multiple antibiotic exposure,
prolonged starvation, exclusively intravenous nutrition, the administration of
vasoactive agents, inhibitors of gastric acidity, and opioids; and finally, the
intense manipulation of the gut, which could disrupt the host-microbe
relationship and thus could yield heightened virulence expression by bacteria
and a fulminant inflammatory response in the host [1,15-18].
INTESTINAL MICROBIOME AND MECHANICAL BOWEL CLEANSING
Mechanical bowel preparation for colorectal surgery has been normal routine for
surgeons for more than a century; however, the Cochrane Database of Systematic
Reviews, in an analysis of 18 trials with 5805 participants aimed at determining
the safety and effectiveness of this preparation on morbidity and mortality in
colorectal surgery patients, concluded that bowel cleansing can be safely
omitted, as it is considered not to reduce rates of surgical site infections,
unless it is combined with both oral and systemic antibiotics [17,19].
By approaching the issue from the perspective of gut bacteria, a randomized
controlled trial evaluated the effect of preoperative mechanical bowel cleansing
on the fecal flora of patients undergoing colorectal surgery. They found a
significant reduction in the total number of bacteria: Clostridium coccoides
group, Clostridium leptum subgroup, Bifidobacteria, total Lactobacillus and
Enterobacteriaceae were found to be significantly reduced, but there was no
effect on the number of Enterococci and Staphylococci [16]. Similarly, from the
16S rRNA gene sequences analysis of mucosal biopsies obtained during
sigmoidoscopies from unprepared and prepared gut of the same individuals, it
became clear that standard colonic lavage alters the composition and diversity
of not only the intestinal lumen microbiota, but also the mucosa-associated, the
differences being more prominent at the genus level [20]. It is now well
accepted that the intestinal luminal and the mucosa-associated microbiota differ
significantly from each other in diversity and composition, and appear as two
distinct ecosystems with different metabolic and immunological functions [21].
Furthermore, when the intestinal microbiota composition was analyzed at
baseline, immediately after bowel cleansing, and after 14 and 28 days, the
number of bacteria in samples collected immediately after bowel cleansing was on
average 34.7-fold lower than at baseline (P<0.001), and the number of
methanogenic archaea was also decreased 20-fold (P<0.001); these had returned to
baseline by the 14- and 28-day samples [22]. So far, it seems that bowel
cleansing could be salutary for patients who are to undergo colon surgery.
However, further analysis revealed that immediately after the lavage, the
intestinal microbiota was significantly different from baseline, even at class
or family level: there was a significant decrease in Bacilli and Clostridium
cluster IV genera and a parallel significant increase in members of the
Proteobacteria phylum and Clostridium cluster XIVa; additionally, the ratio of
Gram-positive to Gram-negative species changed significantly after the lavage
(from 5.3±4.8 to 9.2±7.5 at the 14-day time-point, P<0.05, after which a trend
towards baseline was evidenced), while Proteus genera were still significantly
increased after 28 days (Fig. 2).
Open in a separate window
Figure 2
Alterations of the gut microbiome after mechanical bowel cleansing
In the same manner, a very recently published paper further underlines that,
immediately after bowel lavage, a significant reduction in Lactobacillaceae and
an increase in Enterobacteriaceae abundance were prominent; 30 days later these
families were still significantly lower, while Streptococcaceae had increased
4-fold compared with samples collected before lavage [23].
These recent findings seem to provide clear evidence that the widely used
polyethylene glycol bowel-cleansing preparation could be considered bacterial
genocide, as it has a long-lasting effect on the composition and homeostasis of
gut microbiota. It is well-known that laxatives in general introduce an osmotic
flow of fluids into the gut, washing out the fecal luminal content with a
substantial reduction in intestinal bacteria [24], while the concomitant rapid
increase in gut motility further contributes to flushing out all bacteria
incapable of adhering to the gut mucosa, thus distorting the fecal bacterial
composition [22,25].
Moreover, bowel purgation affects the quality and production of the protective
mucus layer, while the fact that Proteobacteria flourish after lavage and in the
long-term thereafter could be completely explained by the knowledge that purging
leads to the introduction of oxygen into the normally anaerobic ecosystem and to
an increase in pH, via the loss of short-chain fatty acids [25,26].
Finally, it has also been suggested that the sheer mechanical effect of colonic
lavage may alter the intracellular signaling pathways involved in cell
proliferation and influence the interaction between intestinal mucosal cells and
the extracellular matrix, all of which are key elements of the mucosal gut
barrier [27] (Fig. 3).
Open in a separate window
Figure 3
Effects of mechanical bowel cleansing on the intestinal microbiota
INTESTINAL MICROBIOME AND ANTIBIOTICS
Antibiotic administration has long been known to have detrimental effects on the
ecology of commensal bacteria, ranging from self-treated “functional” diarrhea
to life-threatening pseudomembranous colitis [28,29]. Recent studies have
demonstrated that beyond the prolonged disruption of the intestinal microbial
content at the taxa level, antibiotics also affect gene expression, protein
activity and more than 87% of all metabolites, thus deranging the majority of
metabolic pathways of critical importance to host physiology. They have also
underlined that antibiotics lead to a significant alteration of the gut
microbiome and a parallel decrease in microbial diversity of between one fourth
and one third [12,30-32].
Today, it is more or less clear that even short-term antibiotic treatment can
cause detrimental damage to the intestinal microbiome that can last more than 24
months. Panta et al [32] investigated the number and composition of the fecal
microbiota just before and after a 7-day treatment in 21 patients who received
fluoroquinolones, β-lactams and other commonly used antibiotics. Quantitative
polymerase chain reaction analysis and pyrosequencing of the 16S rRNA gene
reveal that both fluoroquinolones and β-lactams significantly decrease microbial
diversity by 25%, reducing the core phylogenetic taxa from 29 to only 12. At the
phylum level, both antibiotics resulted in a 2.5-fold (P=0.0003) decrease in
Firmicutes and an increase in Bacteroidetes, although this phenomenon was not
prominent after treatment with piperacillin/tazobactam and
levofloxacin/metronidazole.
Earlier studies showed that, during a 10-day amoxicillin-clavulanic acid
administration, Bifidobacterium spp. (one of the major groups seen on day 0)
disappeared as early as day 4, and had not returned by day 24. In contrast,
Enterobacteriaceae (which represented only 2% of the day 0 sequences) increased
to 34% on day 4, but were partially restored, as were the other major bacterial
clusters, on day 24 [33]. Similarly, during a 5-day amoxicillin treatment, the
dominant species presented on day 0 showed a major shift starting from day 1,
reaching an average similarity of only 74% after 4 days, after which they were
partially restored to 88% on day 30 and to 89% only on day 60 [34].
Finally, a 5-day ciprofloxacin administration was found to reduce the intestinal
microbiota diversity, with significant effects on about one third of the
bacterial taxa [31], the effects being less pronounced than those of clindamycin
or amoxicillin-clavulanic acid [35]. This taxonomic disturbance had recovered to
almost the pre-treatment state at 4 weeks post-treatment, but several taxa
failed to recover within 6 months [31].
OTHER INTERVENTIONS
Today, it is generally known that many of the infectious bacteria species
acquire the capacity not only to recognize stress-related hormones, but also to
synthesize the very same neurochemicals, which can influence the host. In other
words, pathogenic bacteria in the stressed host may use stress-released hormones
as environmental cues by which to sense their surroundings [36,37]. It is also
well known that microbes constantly assess their microenvironment and alter
their phenotypic expression to optimize their survival, which means they tightly
modify the expression of virulence in response to specific environmental cues
[4,10].
It has been shown that catecholamines directly affect the growth and expression
of virulence-related factors in some bacteria, such as Yersinia enterocolitica,
Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Salmonella
typhii or Campylobacter jejuni [38,39]. Furthermore, there is evidence that the
in-vitro growth of the respiratory pathogen Bordetella bronchiseptica (B.
bronchiseptica) is greatly enhanced in the presence of norepinephrine and that
this ability is, in part, mediated by the ability of norepinephrine to increase
the acquisition of transferrin-bound iron by B. bronchiseptica [40]. In the same
manner, norepinephrine was found to increase the proliferation of Streptococcus
pneumoniae by assisting the delivery of iron from host iron-binding proteins,
while at the same time enhancing the formation of biofilms and thus increasing
antibiotic resistance [39].
Morphine is produced endogenously during the inflammatory processes by different
cell types, including neutrophils, which rapidly transfer it to sites of
inflammation and infection [41]. Additionally, morphine, one of the most
commonly used analgesics, is considered a powerful immunosuppressant [42];
therefore, the sustained exposure of tissues to morphine, either endogenously
produced or exogenously supplied, is a virtual certainty for all surgical
patients, those with trauma, or the critically ill.
Morphine treatment in mice whose gut had been contaminated with P. aeruginosa
caused a shift towards a more virulent phenotype of P. aeruginosa, able to cause
lethal gut-derived sepsis, and a tendency for biofilm formation, thus increasing
its antibiotic resistance. Moreover, P. aeruginosa possesses the ability to
switch phenotype from being mucus-enhancing to mucus-suppressing - having the
ability to destroy gut epithelial integrity - depending on the presence or
absence of morphine [43]. Additionally, Banerjee et al [44] have very recently
shown for the first time that chronic morphine treatment significantly alters
the gut microbiome composition and induces a preferential expansion of
Gram-positive as well as a reduction in bile-deconjugating bacterial strains.
Last but not least, food restriction, even in the setting of complete
intravenous nutrition, leads to a scarcity of macronutrients for the bacteria
within the gut, and thus to a relative loss of Firmicutes and to an expansion of
Proteobacteria and Bacteroidetes. The hostile environment may favor
Proteobacteria, because they have been shown to survive in states of relative
starvation, versus Firmicutes, which dominate in a nutrient-rich environment
[45,46]. Furthermore, a micronutrient insufficiency in the host, such as a lack
of iron and phosphate, results in an analogously deprived environment, and it is
well-known that local tissue phosphate concentration functions as an important
cue through which endogenous bacteria “taste” the resources of the host to
determine whether they should colonize or invade the host [4].
DECREASED MICROBIAL DIVERSITY, VIRULENCE AND POSTOPERATIVE COMPLICATIONS
It is increasingly recognized that the gut microbiome plays a fundamental role
in the health maintenance of the host, and that any alteration in the diversity,
the number or the virulent phenotype can have a critical effect on host
morbidity and even mortality. The concept that bacteria are able to sense the
host environment, and adjust their behavior and virulence accordingly, is a new
dimension in the area of intense research in severe-infection patients that
breaks new ground in our understanding of how the gut acts as the driving force
of critical illness [47]. Based on these observations, it is obvious that when,
for whatever reason, the symbiotic relationship with the host is turned to
dysbiosis, the newly pathogenic bacteria can further trigger and promote harm to
the already compromised host, in a positive spiral feedback.
Since medical interventions and surgical manipulation of the host are part of
everyday practice, it would be of great interest and importance to examine the
precise mechanisms and correlate the reported alterations of the microbiome with
the infectious complications in the surgical and/or critically ill patient.
Shimizu et al [3,13] found a significant reduction in the total anaerobic
bacteria, as well as 2-log higher counts of the hazardous Staphylococcus and
Pseudomonas groups, in the fecal flora of patients with SIRS, compared to
healthy volunteers. Furthermore, they correlated key bacteria in the gut and
derived their cutoff values in relation to infectious complications and
mortality. The equilibrium between obligate anaerobes and total facultative
anaerobes seems to play a critical role in causing septic complications: during
the unfavorable evolution of SIRS, alterations in gut bacteria usually progress
from a diverse pattern to a single pattern and then on to a depleted pattern,
the three types representing a continuum of abnormality, depending on the
severity of the patient’s condition. Bacteremia was evident in 35% of those with
a diverse pattern versus 71% with the single pattern, resulting in a mortality
rate of 6% in the former, 52% in the letter, and 64% in those with a depleted
pattern (P<0.05) [48].
Liu et al [49] analyzed the feces of patients undergoing colorectal surgery and
found a reduction in microbial diversity, including Bifidobacteria and
Lactobacilli. In contrast, the numbers of Enterobacteriaceae, Pseudomonas and
Candida, showed a significant increase, which in turn was well correlated with
the higher rate of infectious complications, 46% versus 14%, in
probiotics-treated patients (P<0.05). Likewise, Komatsu [50] reported a
significant reduction in the total number of bacteria and the number of dominant
obligate anaerobes and a significant increase in the number of
Enterobacteriaceae, Staphylococcus (MSCNS), Pseudomonas, and Clostridium
difficile after colorectal surgery, compared with data from the same group
before surgery.
Finally, in a recent study, neonatal piglets that underwent intestinal resection
and received parenteral nutrition and antibiotics or placebo were examined at
day 7 against age-matched sow-fed piglets. Ileal and colonic contents revealed
dramatic differences in diversity and an almost complete loss of Lactobacillus,
along with a remarkable increase in the Fusobacteriaceae and Enterobacteriaceae
families in both the ileum and the colon. In addition, there was an increase in
the Bacteroidaceae family in the colon [51]. These results strongly support
similar findings in humans undergoing small bowel resection, who lacked exposure
to enteral nutrition for 2 weeks. The reported loss in fecal bacterial diversity
in this study was clearly associated with a higher incidence of postoperative
infectious and anastomotic complications [52].
ANASTOMOTIC LEAKS
In colorectal surgery, an anastomotic leak represents the most dreaded of all
complications, since it is often perceived as a failure of the operation or the
surgeon, although the real cause of dehiscence is not fully elucidated. However,
it has long been known that the intestinal bacterial population plays rather an
important role: inoculation of rats with 109 P. aeruginosa led to an increase in
the incidence of anastomotic insufficiency up to 95% after gastrectomy and to a
significant increase in mortality [53].
This concept has re-emerged as a result of advances in microbial isolation and
identification using 16S rRNA analysis. Olivas et al [54], working in an rat
model of preoperative irradiation plus colonic resection and anastomosis,
demonstrated that intestinal colonization with P. aeruginosa resulted in a
significantly higher incidence of leaks, compared to the non-colonized group.
What is even more striking is that the Pseudomonas colonizing anastomotic sites
had become, in vivo, transformed to express a tissue-destroying phenotype; that
is, one that had undergone a single nucleotide polymorphism mutation in the mexT
gene that resulted in a much more virulent phenotype with increased collagenase
activity, high swarming motility, and an increased ability for tissue
destruction.
It is well known that important human mucosal pathogens have evolved virulence
mechanisms to circumvent the mucosal epithelium barrier [55,56]. P. aeruginosa
seems to favor damaged epithelial tissues to initiate colonization [57]; then,
upon binding to epithelial cells, it activates a phosphatidylinositol 3-kinase,
which is absolutely necessary for P. aeruginosa to enter from the apical surface
of polarized epithelial cells, by subverting the epithelial cell polarity [56].
Further studies have demonstrated that the anastomosis construction itself
causes significant alterations to the bacterial composition at the anastomotic
site, but not to the luminal microbial content [58]. The most interesting
observations are that the Enterococcus and the Escherichia/Shigella populations
increased by 500-fold and 200-fold, respectively; at the same time, populations
of beneficial bacteria were reduced [59,60]. For an in-depth analysis of the
marked Enterococcus increase [58] and the associated high collagen-degrading
activity, they inoculated Enterococcus faecalis (E. faecalis) strains obtained
just after completion of the colorectal anastomosis in a rat model and on the
sixth postoperative day; by collecting the liquids drained from the gut, they
demonstrated that the collagen-degrading activity of the bacteria recovered from
the anastomotic area enabled discrimination between leaking and non-leaking
anastomotic sites. They also found that E. faecalis exhibited an increased
ability to activate tissue matrix metalloproteinase-9, operated through the gelE
and sprE genes, both of which contributed to anastomotic leakage [61].
The microbiome of eight patients who experienced colorectal anastomotic rupture
and of another eight matched for age, gender and adjuvant therapy, was
investigated by studying the rings of colon and rectum tissues cut by the
circular stapler to make the anastomosis [62]. The investigators surprisingly
reported a significantly higher proportion of the Lachnospiraceae family versus
controls-although these bacteria tend to be rather friendly to the bowel, as
most of them belong to butyrate producing genera. However, further analysis
revealed that a large fraction of the Lachnospiraceae were identified to be of
the mucin-degrading Ruminococcus, and that Lachnospiraceae levels were strongly
negatively correlated with microbial diversity levels, which in turn are
associated with anastomotic leakage.
Go to:
PROBIOTICS - PREBIOTICS - SYNBIOTICS
Probiotics are live microbial food supplements that may beneficially affect the
host by improving its intestinal microbial balance, while prebiotics are
indigestible fibers that promote the growth and function of probiotics; their
combination is called synbiotics [7]. Probiotics are able to maintain gut
barrier function by restoring intestinal permeability and ameliorating the
intestinal inflammatory response and the release of cytokines, and can also
maintain the homeostasis of the normal gut microbiota. As a result, they have
been extensively studied as an adjuvant perioperative treatment modality for
surgical patients [7,11]. In the field of gastrointestinal surgery, it has been
shown that probiotics may be effective in restoring gut microbiota diversity,
enhancing immunological response, reducing the systemic inflammatory response
released postoperatively, and improving patients’ quality of life. Moreover, as
a consequence of all the above, they appear to work positively in reducing the
total length of hospital stay, the number of days of ventilator support required
and of days in intensive care, and the overall infectious complications [63-66].
However, other investigators have reported no benefits after the perioperative
use of probiotics in patients undergoing elective abdominal surgery. A possible
explanation of these differences may be related to the rather short
administration period (median of 4 days) in the majority of the studies, the low
concentration of bacteria present in the formulation prescribed, the one
probiotic strain only of the regimen used, and the small number of participants
in most studies. Last but not least, consideration must be given to the open-gut
manipulation strategies applied, which fortify the bacterial contamination of
the peritoneal cavity and the interruption of blood supply to the viscera, due
both to the ligation of major vessels and the use of heat-coagulation for the
smaller ones [67,68]. Finally, many clinicians start with the negative
assumption that, given the degree of diversity and metabolic functions of the
normal core microbiome, it appears naïve to believe that some Lactobacilli
strains could fully supplant the degree of functionality required of the
intestinal microbiome to bolster systemic immune function during disease states.
PROBIOTICS AND INFECTIOUS COMPLICATIONS
Multiple studies have been performed regarding the potential benefit of enteral
administration of probiotics in reducing infectious complications in surgical as
well as in critically ill patients, based on the idea that they may modify the
gastrointestinal bacteria in a manner that preferentially favors the growth of
minimally virulent species [69]. He et al [68] analyzed six randomized
controlled trials dealing with pro/synbiotic administration in 361 colon cancer
patients undergoing colorectal resection and found a significant decrease in the
total number of infections (P=0.001), mainly due to the decreased cases of
pneumonia (P=0.04), while other infectious complications, such as surgical site
or intra-abdominal infections or bacteremia, remained unaffected.
This is in line with a previous meta-analysis that demonstrated a significant
reduction in the rate of nosocomial pneumonia (P=0.03) in critically ill
patients treated with probiotics [70], as was also reported in relation to
ventilator-acquired pneumonia (VAP) [71]. Various other studies have
demonstrated similar effects, while a recent meta-analysis suggests that
probiotic treatment results in a 39% reduction in VAP, along with a subsequent
reduction in the length of ICU stay [72]. A possible mode of action is
considered to be the ability of probiotics to inhibit or ameliorate
gastrointestinal and systemic bacterial colonization [73], since it has been
shown that probiotic-treated patients exhibit smaller rates of P. aeruginosa
colonization versus controls [72]. In a meta-analysis of 5 trials (844
patients), probiotics showed a trend towards a lower incidence of VAP; when one
trial was excluded, a statistically significant conclusion could be drawn. Thus,
the administration of probiotics seems to significantly reduce the risk of VAP
caused by P. aeruginosa [74].
Another study suggested that modification of the upper aerodigestive flora by
means of applying probiotics could reduce nosocomial infections [69]; in any
case, Lactobacillus administration resulted in a significant delay in the time
to onset of VAP (P<0.001), as has also been documented in a study of our group,
where a statistically significant delay in the time of blood infection onset was
prominent [75].
In a randomized controlled study of colorectal cancer patients, Zhang et al [64]
demonstrated a significant reduction in septic complications (33.3% in controls
versus 10% in probiotic-treated), along with a significant decrease in E. coli
and a significant increase in the Bifidobacterium counts in the same group.
Likewise, fecal cultures in ICU multiple trauma patients, symbiotic-treated,
revealed a decrease in Enterobacteriaceae, coagulase-negative Staphylococci, and
Gram-negative anaerobes, and an increase in Enterococcus spp. and Gram-positive
anaerobes [76]. These patients demonstrated a 13.9% incidence of bacteremia
versus 36.1% in those receiving placebo (P=0.028), a finding related to the
reduced incidence of Acinetobacter baumanii-related, ventilator-associated
pneumonia [77]. Various other studies have produced similar results, with Liu
[78], in a study of colorectal cancer patients, reporting rates of bacteremia of
55% in the probiotics group versus 72% in controls, P=0.017.
Furthermore, a recent meta-analysis demonstrated a reduction of postoperative
sepsis after elective general surgery, both in pro- and synbiotic-treated
patients compared to placebo (P=0.003 and 0.002, respectively). However, no
significant difference in the incidence of pneumonia, urinary tract or surgical
site infections was found [79], while a very recently published study revealed a
significant decrease of 38% in the incidence of postoperative sepsis. Separate
analysis according to the type of operation revealed a statistically significant
difference among the types, with a 35% risk reduction in colorectal surgery, 73%
in hepato-pancreatico-biliary, and a 56% risk reduction in liver transplant
operations; these findings add to the evidence that colorectal surgery patients
might be the most difficult group for the manipulation of gut microbial balance
[80].
Finally, in a recently conducted systematic review, the mean incidence of
surgical site infection was 6.8% in treated patients and 11.1% in controls,
representing a 37% reduction. This study also underlined the potential benefit
in relation to urinary tract infections and composite infections, as well as the
non-occurrence of serious adverse events related to study products [81].
Moreover, it is now common knowledge that, because of the complexity of the
individual gut microbiome, probiotics are not a one-species-fits-all approach
[82]; thus, when a single probiotic regimen (Lactobacillus plantarum [L.
plantarum] 299v) was used in patients undergoing colectomy, no benefit was found
regarding postoperative complications [67].
PROBIOTICS AND COLON ANASTOMOSIS FAILURE
Taking into account the further progress in the research of Shogan et al [58],
demonstrating that anastomosis construction itself causes significant
alterations to the bacterial composition at the anastomotic site, and the recent
knowledge that all medical and surgical interventions related to anastomosis
construction contribute to a reduction in bacteria diversity, including the
eradication of beneficial and the increasing virulence of noxious species
[54,61], it is reasonable to seriously reconsider the crucial role of bacteria
in undermining the healing process and to look for a mode of enrichment of the
scarce or destroyed bacterial species, the simplest and easiest mode being
probiotics.
The first single-center randomized clinical study to evaluate the effect of
probiotic treatment on the incidence of colon anastomotic failure was that of
Zhang et al [64]. They demonstrated only a slight reduction in the rate of
anastomotic leaks (0/30 in probiotics-treated individuals versus 2/30 controls
(P=0.49). However, the patients had received 3 oral viable capsules/day for 3
days only (108 cfu/g of Bifidobacterium longum, Lactobacillus acidophilus [L.
acidophilus], and E. faecalis), from day -5 to day -3, followed by conventional
bowel preparation plus oral gentamicin for 3 days.
In a recent randomized study by our group, involving patients undergoing
colorectal surgery for cancer, a four-probiotic formulation (L. acidophilus, L.
plantarum, Bifidobacterium lactis and Saccharomyces boulardii) or placebo was
administered, starting one day before surgery – after mechanical bowel cleansing
– and continuing for 15 days postoperatively, the patients being followed-up for
complications for 30 days. The probiotic-treated group exhibited a significantly
lower rate of all postoperative major complications (28.6% versus 48.8% in the
placebo arm, P=0.010), postoperative pneumonia (2.4% versus 11.3%, P=0.029),
surgical site infections (7.1% versus 20.0%, P=0.020), and anastomotic leakage
(1.2% vs. 8.8 %, P=0.031) [63].
Moreover, after total RNA extraction, it was also clearly found that in
probiotics versus controls, there was modulation of suppressor of cytokine
stimulation-3 (SOCS3) expression which encodes for the protein SOCS3 that
finally suppresses overwhelming cytokine responses. In other words, the
prophylactic action of probiotics in these colon-cancer patients is exerted
through modulation of the immune response and is linked with the prevention of
immunosuppression development after a bacterial challenge [64].
From all the above analyses, we would summarize that exogenously given
probiotics contribute at least partially to the restoration of the decreased gut
microbial diversity, but mainly preserve the host’s immune function; i.e., they
prevent immunosuppression, which might otherwise be “detected” by the pathogens
and trigger changes in their virulence and lethality as they then attack the
host.
Go to:
CONCLUDING REMARKS
Modulation of the intestinal microbiota with probiotics seems to be an effective
method of reducing infectious complications in surgical patients, although their
effect on mortality has still not been elucidated. Further studies need to be
conducted to establish the best possible combination of probiotics, as well as
to determine the subgroup of patients who could benefit most from such an
intervention.
Go to:
BIOGRAPHY
•
Aristotle University of Thessaloniki, Thessaloniki, Greece
Go to:
FOOTNOTES
Conflict of Interest: None
Go to:
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synbiotics for the prevention of postoperative infections following abdominal
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* Abstract
* Introduction
* Intestinal microbiota: symbiosis and dysbiosis
* Probiotics - prebiotics - synbiotics
* Concluding remarks
* Biography
* Footnotes
* References
--------------------------------------------------------------------------------
Articles from Annals of Gastroenterology are provided here courtesy of The
Hellenic Society of Gastroenterology
--------------------------------------------------------------------------------
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Eleftheriadis E. Benefits of a synbiotic formula (Synbiotic 2000 Forte) in
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treatment on serum zonulin concentration and subsequent postoperative infectious
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the gut microbiome improve clinical outcome? JPEN J Parenter Enteral Nutr.
2013;37:243–253. [PubMed] [Google Scholar] [Ref list]
80. Arumugam S, Lau CS, Chamberlain RS. Probiotics and synbiotics decrease
postoperative sepsis in elective gastrointestinal surgical patients: a
meta-analysis. J Gastrointest Surg. 2016;20:1123–1131. [PubMed] [Google Scholar]
[Ref list]
81. Lytvyn L, Quach K, Banfield L, Johnston BC, Mertz D. Probiotics and
synbiotics for the prevention of postoperative infections following abdominal
surgery: a systematic review and meta-analysis of randomized controlled trials.
J Hosp Infect. 2016;92:130–139. [PubMed] [Google Scholar] [Ref list]
82. Tappenden KA. Probiotics are not a one-species-fits-all proposition. JPEN J
Parenter Enteral Nutr. 2012;36:496. [PubMed] [Google Scholar] [Ref list]
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