Author’s Accepted Manuscript

Influence of the intestinal microbiome on

anastomotic healing in the colon and rectum

Connie Shao, Sara Gaines, John C Alverdy

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PII: S1043-1489(17)30069-6
DOI: http://dx.doi.org/10.1053/j.scrs.2017.09.001
Reference: YSCRS615
To appear in: Seminars in Colon and Rectal Surgery
Cite this article as: Connie Shao, Sara Gaines and John C Alverdy, Influence of
the intestinal microbiome on anastomotic healing in the colon and rectum,
Seminars in Colon and Rectal Surgery,
http://dx.doi.org/10.1053/j.scrs.2017.09.001
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Influence of the Intestinal Microbiome on Anastomotic Healing in the Colon and Rectum

Connie Shao BS, Sara Gaines MD, John C Alverdy MD

Connie Shao BS, Medical Student

Sara Gaines MD, General Surgery Resident

John C Alverdy MD, Professor of Surgery, Director of Center for the Surgical Treatment of

Obesity, Director for Minimally Invasive Surgery and Surgical Treatment of Obesity Programs

From the Department of Surgery, The University of Chicago, The Pritzker School of Medicine,

Chicago, IL

Supported in part by Ruth L. Kirschstein National Research Service Award – T32 Institutional

Training Grant, awarded to Sara Gaines MD, from the Digestive Disease Research Core Center,

University of Chicago Medical Center

Correspondence address:

Sara Gaines, MD

5841 Maryland Ave, MC 6090

Chicago, IL 60025

Phone: 828-234-9886

Fax: 773-834-0201

Sara.gaines@uchospitals.edu
ABSTRACT

Colonic and rectal anastomotic leak has long plagued the surgeons, without much

improvement despite decades of advances in suture technique and technology. At the intersection

of microbiotal changes in flux via a combination of environmental factors and the virulent

pathology of the organisms colonizing the gastrointestinal tract, lies an underappreciated

mechanism and thus possible solution for anastomotic failure. Through pre-operative

preparation, intra-operative manipulation, and post-operative management, the flora is constantly

changing. This article explores the shifts in composition and expression of the digestive flora in

response to external factors and the effects thus far observed on anastomotic healing, as well as

proposed therapeutic strategies given the leading theories on microbiotal pathogenesis of

anastomotic leak.

Key words: Microbiome, Anastomosis, Anastomotic Leak, Colonic Resection, Colorectal Cancer
INTRODUCTION

Although colon surgery has never been safer as a result of improvements in surgical

technique, anesthesia, and postoperative care, the possibility of an anastomotic leak (AL)

remains a real and present threat to even the most skilled and experienced surgeon. While

multiple studies suggest that leak rates are at a historical low, between 3 and 8% in high volume

centers of excellence (1-2), many if not most of such leaks are only included in the analysis when

symptomatic enough to elicit imaging. In many cases, unless therapy is required, leaks may not

be included in the final tally at all. Finally, as a result of the liberal use of a protective stoma,

many leaks in high risk patients go undetected and therefore opportunities to understand the

pathobiology that underpins AL remain few to non-existent (3-4).

AL has been traditionally framed as a failure to apply adequate surgical technique

involving factors such as suture placement, device deployment, tension, and ischemia. When

technique cannot be ascribed as a proximate cause of leak, patient-related factors are often

invoked, such as malnutrition, exposure to radiation and chemotherapy, obesity, and use of

tobacco. Yet an overlooked and unexplained occurrence in this type of deductive reasoning is the

consistent observation that the majority of such high risk patients (i.e >80%), in fact, do not

develop the clinical manifestations of an AL. Whether this is due to the liberal use of a protective

stoma in such patients or other factors remains unknown and highly controversial.

As a result of the pervasive notion that ALs are more a function of the physics of

anastomotic construction than the biology of healing, multiple attempts continue to address

methods to improve anastomotic technique by varying of suturing placement (distance, layers,

tension, configuration, etc) or stapling in an end-to-end versus end-to side fashion, using

extraluminal sealing with fibrin glue or acrylates or applying internal shields to protect
anastomotic tissues from the fecal stream. In the aggregate, none of these approaches has been

shown to be effective at preventing AL; in fact some have been shown to lead to higher leak

rates (5-6).

THE INTESTINAL MICROBIOME AND ANASTOMOTIC HEALING

Although a significant body of evidence exists to suggest that the presence of the normal

microbiota actually promote anastomotic healing in animals (REF), in humans, as a result of the

use of broad spectrum antibiotics, evidence suggests that their presence is actually harmful to

anastomotic healing. For example, Cohn first proposed in 1955 that the microbial contents of the

gut plays a central role in the pathogenesis of AL. He found that when dogs undergoing

anastomotic surgery were treated with a direct intraluminal infusion of tetracycline at the

anastomotic site via an indwelling catheter, AL was prevented in the anastomotic segments that

were rendered ischemic by dividing the supplying blood vessels (7). More indirect evidence by

way of antibiotic administration became available in 1994 from both animals and humans when

investigators again demonstrated that antibiotic decontamination of anastomotic tissues

prevented AL (8).

Unfortunately, the current inability to track changes in microbial environments over the

course of healing makes it difficult to ascertain which aspects of the microbiota, i.e. community

structure, membership, and/or function, should be preserved and which should be eliminated or

contained. Given that we do not know which microbiota are associated with progression to

normal healing and which cause poor healing, we continue to use a broad coverage approach to

kill most of the microbes in the gut. Yet, progress has been made with culture independent

methods, such as molecular techniques, as the majority of species within our microbiome are not

able to be cultured (9). This approach may allow us to better understand how to direct therapy
against harmful microbes while preserving the health benefits of the probiotic flora.

Of the intestinal bacteria that are able to be cultured and identified, there are four main

phyla. More than 90% of the bacterial cells are composed of Firmicutes and Bacteroides, with

the rest mostly composed of Actinobacteria and Proteobacteria. (10) These are the bacteria that

constitute the complex microbiome of over 1014 microbes, consisting of 500-1500 species. It’s an

ecosystem that remains relatively stable despite the constant fluxes in external exposures and

dietary changes. The genetic material within these microorganisms is what encompasses the

entire biomass of the the human microbiome (11).

Due to changes in the nutritional availability and chemical networking from the

microbiota itself, the composition of intestinal flora varies from location to location. The small

intestine harbors Proteobacteria and Lactobacillales due to the high availability of

monosaccharides, disaccharides, and amino acids. Simple sugars are absorbed by host cells in the

distal small intestine, resulting in a distinct bacterial composition. The complex carbohydrates

that persist beyond the ileocecal valve are not able to be digested by the host, nor are

Proteobacteria like Escherichi coli, resulting in abundance of Bacteroides and Clostridiales that

can break down polysaccharides like fiber (12).

The major function of the resident microbiota within the gut is to protect the intestinal

epithelium from colonization of disruptive pathobionts. These microbes also have profound

systemic effects on human physiology, such as culling energy and vitamins from food (13-14),

differentiation and growth of epithelial cells (15), development and homeostasis of the immune

system (12), and keeping noncommensal organisms at bay (16). However, when this

environment is disrupted, local cytokines, inflammatory, markers, and the ability to heal are

affected.
 The specific species and molecular mechanisms that underpin AL are still being

elucidated, although some species have been identified that can have significant effects on

anastomotic tissues. A study in 2015 showed that the low abundance commensal Enterococcus

faecalis, can contribute to the pathogenesis of AL by activating tissue matrix metalloproteinase 9

in host intestinal tissues and increasing collagen degradation in a devascularized environment.

AL was prevented through the use of topical antibiotics applied to the intestinal tissue or

pharmacological suppression of intestinal MMP9 activation, although not with intravenous

antibiotics (17).

During surgical injury, soluble products are released that can act as chemoattractants and

induce phenotypic shifts among pathogenic bacteria such as Pseudomonas aeruginosa. This shift

allows for the in vivo expression of an adhesive phenotype among colonizing pathogens, helping

explain how their presence may shift the local environment to result in injured tissue. Both from

the use of antibiotics and the antibiotics that pathogens such as Pseudomonas themselves release,

cytoprotective microbiota are lost, including Firmicutes and Bacteroidetes, allowing for the

proliferation of, and colonization of tissues by, pathogenic organisms. With germ-free and

antibiotic-treated animals, disruption of normal microbiota results in a weaker intestinal

anastomosis, as measured by the pressure needed for an anastomosis to burst (18).

CHANGES TO THE COLONIC MICROBIOME

Lifestyle choices, known risk factors for the development of AL, such as diet, exercise,

and environmental exposures like smoking or pets have been shown to have significant and

specific effects on the microbiome although overall composition may appear stable (19). Major

physiological stressors such as surgery or a major burn injury can dramatically change the gut

microbiota in as little as 6 hours (9). As such, the quantity, structure, membership, and function
of the intestinal microbiome can be significantly affected by multiple factors that may be highly

individualized in a given patient. In light of these emerging insights from the study of the

microbiome, our current approach to prepare the bowel for intestinal surgery may suffer from a

lack of fundamental science and use of next generation technology to explain what we are doing

right and what we may be doing wrong.

Mechanical bowel preparation

Bowel preparation is the reduction of fecal load through either an osmotic agent (e.g.

polyethylene glycol, sodium phosphate) or a stimulant (e.g. sodium picosulphate). Osmotic

agents can be metabolically inert, such as polyethylene glycol, or hyperosmolar, such as sodium

phosphate. Polyethylene glycol requires the ingestion of large quantities of liquid, which can

result in adverse side effects such as nausea and vomiting, risking low compliance, though has

fewer side effects than hyperosmolar solutions (20-21). Stimulants induce colonic contractions

and are usually combined with the osmotic agent magnesium citrate to retain fluid in the colonic

lumen. The electrolyte disturbances induced by stimulant agents have been shown to require the

ingestion of at least 2 liters of water to compensate for water secretion in the colon (22). The

clearing of bulky matter may also result in mucosal inflammation detectable only by histology,

most notable for loss of superficial mucus and epithelial cells as well as inflammatory changes

with lymphocytic and polymorphonuclear infiltration (23). These mucosal changes have been

suggested to influence the interactions between cells and the extracellular matrix, affecting the

intracellular signaling for cell proliferation (24).

With an environment in flux within multiple dimensions, including movement,

electrolytic environment, fecal load, and hydration status, it seems likely that there would be

significant and potentially adverse changes in the microbiome during its preparation for surgery.
In fact, the number of bacteria collected immediately after bowel cleansing has been found to be

on average 34.7 times lower than at baseline (p<0.001), but were found to return to baseline

within several weeks (25). Even the composition of bacteria was changed, with a significant

decrease in Bacilli and Clostridium and an increase in Proteobacteria. The increase in

Proteobacteria after lavage can be explained by the introduction of oxygen into the normally

anaerobic environment and an increase in pH from the loss of short chain fatty acids (26-27).

Given that Proteobacteria (i.e gram negative bacteria) are often the most pathogenic of the

intestinal microbiota, this finding deserves further investigation.

Statistically significant changes in gut flora are observed depending on the duration of

mechanical bowel preparation. A study in 2012 found that Bifidobacterium and Lactobacillus

were found to be decreased significantly, more so with 1 day of bowel preparation than with 3

days. E. coli and Staphylococcus sp. were found to be higher than the preoperative level, more

significantly so in patients who had 3 days of bowel preparation. Post-operative infection was

found to be significantly lower when bowel preparation was performed over 3 days than with 1

(28). While there are many confounding factors with this study, such as the procedure itself, the

differences that occur in the gut flora with variations in bowel preparation beg a more complete

understanding of its clinical impact.

A Cochrane Database of Systematic Reviews found that bowel cleansing can be safely

omitted without affecting the morbidity or mortality in colorectal patients, as it did not reduce

rates of surgical site infections unless it was combined with both oral and systemic antibiotics

(29-30). This study and others are not in line with current standard practices. In fact, this line of

inquiry is in flux and begs a more complete understanding of how to prepare the bowel through a

higher resolution genetic analysis of the microbiome. This finding suggests again that it is the
microbial changes, and not the actual bowel preparation itself, that needs to be mapped to the the

post-surgical outcomes in colorectal patients.

Antibiotics

The pathogenesis of Clostridium difficile best explains the narrative of how the empirical

choice and promiscuous use of antibiotics can lead to adverse outcomes. Treating a bacterial

infection with an antibiotic such as clindamycin can result in the proliferation of an otherwise

benign bacterial species, allowing it to run rampant and wreak havoc in the form of horribly

persistent watery diarrhea. Similarly, the prophylactic administration of antibiotics, either orally

or intravenously, alters the normal physiologic symbiosis of the gut microbiota, resulting in an

altered ecosystem whose normal healing abilities may be diminished. In addition to affecting the

microbial content of the gut microbiome in the form of diversity diminution, antibiotics can also

affect microbial genetic expression, protein activity, and metabolites. Such shifts have the

potential to create an entirely new and foreign source of resources from which the mucosal cells

must find a means to heal (31).

There have been many studies elucidating the specific changes in the microbiome that

occur as a result of the use of specific antibiotics (32-33). It is most important to note that even

short term antibiotics can have a long lasting impact with reductions in both diversity and

quantity of the normal microbiota. For example, after a 5-day administration of amoxicillin, the

percentage similarity of the dominant species that presented on day 0 was only at 89% by day 60

(34). A five-day administration of ciprofloxacin was found to have taxonomic disturbances that

persisted beyond 6 months (35).

Skin decontamination with oral and IV antibiotics

Among the many goals of preparing the bowel for intestinal surgery, included is the
prevention of surgical site infections, presumed to be caused by intraoperative wound

contamination. Surgical site infections (SSIs) are a devastating and common complication of

hospitalization, occurring in 2% - 5% of patients undergoing surgery in the United States.

Staphylococcus aureus is the most common cause, occurring in 20% of surgical site infections

among hospitals that report to the Centers for Disease Control and Prevention (CDC) and causes

as many as 37% of SSIs that occur in community hospitals (36). While topical transmission is

the likely contributor, other mechanisms may be a play. For example, a Trojan Horse hypothesis

of MRSA wound infection has been proposed whereby gut colonization by MRSA can lead to

the pathogen traveling inside a neutrophil from the gut to the wound causing clinical wound

infection. This was demonstrated in mice where antibiotic treatment and oral labeled MRSA

gavage caused remote MRSA wound infection with gross abscess formation by a process in

which the MRSA is picked up in the gut and delivered to the wound inside a neutrophil (37).

Such interorgan pathogen transfer from gut to wound suggests that a more complete

understanding of how to prepare the bowel for surgery may be in order. This may involve

understanding which pathogens persist in the gut when a broad-based anti-microbial regimen is

used to both debulk and eliminate the microbial contents of the gut.

There are multiple influences that shape the gut microbiome beginning at birth, which are

generally not accounted for when considering how to prepare the bowel for surgery. In fact, the

very age of the patient may need to be considered as the intestinal and skin microbiome

composition have been recently shown to be age-dependent (38-39). In children, for example,

this is an effect largely made significant by the development of neonatal immune systems via the

colonization of skin flora by the mother’s vaginal microbiota at birth. Differences in the mode of

delivery are definitively linked to differences in the intestinal microbiota of babies, a finding that
has been proven repeatedly (40-43). Children born vaginally are colonized predominantly by

Lactobacillus, while those delivered by cesarean section are colonized by a mixture of bacteria

found on the skin and in a nosocomial environment, including Staphylococcus and Acinetobacter

(44). While mechanisms have yet to be elucidated, there are statistically significant connections

between these different floras and the presence of specific diseases, namely atopy and

gastrointestinal disturbances, that persist throughout later years of life.

This example of a direct connection between the topical colonization of skin flora and the

consequent colonization of the gut flora by ingestion of the colonies on their hands may have

significant implications to the hospitalized patient, as has been recently demonstrated in the

hospital microbiome project (45). While it is presumed that health care providers’ hands are the

major vectors for pathogen transmission between patients, this hypothesis not only is difficult to

prove, but may actually be incorrect. Using genetic tracking of bacterial movement, studies are

emerging to suggest that most pathogens that cause serious nosocomial infections, may come

from the patients themselves (REF). Their age, previous healthcare encounters, previous use of

antibiotics, and lifestyle choices may shape their microbial flora, whose response to stressors

such surgery and ischemia may not only be unique, but unpredictable.

Ischemia

Intestinal resection both exposes the typically anaerobic bowel lumen to oxygen while

temporarily interrupting the local blood supply when the supplying blood vessels are ligated.

This can result in the depletion of health-promoting obligate anaerobes such as Bacteroides and

Clostridia, while facultative anaerobes such as Lactobacillus and Enterobacteriaceae flourish.

These changes were first observed in the colons of patients following small bowel

transplantation by comparing the colon flora before and after ileostomy closure. (46). These
finding suggest that there is a key relationship between how surgeons manipulate environmental

factors during surgery and the composition of the intestinal flora.

A study by Wang, et al of the colonic microbiota of rats that underwent 0.5-hour

ischemia and had their bacterial diversity quantified at various time points found that colonic

flora changed early and differed significantly 6 hours after reperfusion, after which they started

to recover. The shifts were largely characterized by an increase of E. coli and Prevotella oralis,

with Lactobacilli proliferation occurring with epithelial healing (9). The proliferation of E. coli

resulted in more significant alteration in cellular morphology and physiology (47-48). During

major intestinal surgery, understanding the composition and behavior of pathogens that remain

on intestinal tissues (i.e anastomoses) over the course of recovery may be just as important as

knowing which are there at the beginning. As can be seen, the empiricism of the current

approach to prepare the bowel for surgery needs a mid-course correction based on emerging

knowledge in microbiome sciences.

Tracking the course of intestinal healing using next generation technology may provide

clues as to how the microbiota influence the healing process. At 6 hours after reperfusion, the gut

flora is observed to be at their highest level of diversity and most altered composition compared

to baseline. The peak in microbial compositional difference at 6 hours also implies that gut

ischemia/reperfusion, a regular occurrence during routine surgery, may have a significant effect

on the luminal microbiota that temporally fluctuates.

Pharmacologic effects

Besides the direct impact on the microbial environment with antibiotics, other

pharmaceuticals used as relatively benign forms of therapy throughout the course of the surgery

and during recovery can impact the microbial composition of the patient’s colon. The use of
antacids in the Dutch community, a country that has low antibiotic use, has been associated with

an increased risk of extended-spectrum-beta-lactamase producing Enterobacteriaceae (49).

Opioid analgesics are commonly used to manage pain after surgery. However, their chronic use

reduces pathogen clearance and induces bacterial translocation across the gut barrier, a process

normally prevented by an intact intestinal microbiome. Many of these concepts and processes

have been addressed by the enhanced recovery after surgery (ERAS) bundle and their

mechanisms of action are coming to light via microbiome sciences.

For example, morphine use, a major target of the ERAS program, has been shown to

significantly alter gut microbial composition, inducing a proliferation of Gram positive

pathogens and reducing bile-deconjugating bacterial strains, resulting in decreased bile acid

levels in the gut (50). Morphine use in rats has been shown to increase the amount of high

collagenase-producing Enterococcus faecalis adherent to anastomotic tissues, correlated with

increased rates of impaired anastomotic healing and gross leaks. In in vitro studies with E.

faecalis isolates, exposure to morphine results in increased adhesion and collagenase production,

regardless of baseline collagenase production (51). Morphine has also been found to cause a shift

toward a more virulent phenotype of P. aeruginosa, forming a biofilm of increased antibiotic

resistance that is able to cause lethal sepsis. Finally, morphine can alter intestinal mucus and

destroy gut epithelial integrit. Therefore, in the aggregate, these observations suggest that its

judicious use or avoidance after surgery, as proposed by ERAS, is scientifically rational (52).

INCORPORATING MICROBIOME SCIENCES IN PRACTICE TO REDUCE

ANASTOMOTIC COMPLICATIONS

Further research is needed to more completely elucidate the molecular mechanisms that

drive complete and uncomplicated anastomotic healing. Simply culturing expelled stool and
testing for antibiotic resistance is inadequate. Phenotype characterization is essential to

understanding how commensal bacteria transform in vivo in response to the ever-changing and

individualized environmental factors that can influence the expression of novel traits of virulence

or pathogenicity. This will require next generation technology in order to guide practice. Bacteria

are promiscuous gene-swapping organisms and through horizontal gene transfer, phenotype

switching, and bacteriophage transmission, the exact actions of different microbial organisms

cannot be understood without an in-depth molecular analysis. This approach is now becoming

cheaper, faster and more readily available. Bioinformatic analysis and graphic display are also

developing into readouts that can be easily understood by non-research clinicians.

Current practice for preparing the bowel for surgery includes a mechanical bowel

preparation, broad spectrum antibiotics as prophylaxis, and topical decontamination. In practice,

utilization of these methods is highly variable as is the selection of antimicrobial agents. A more

complete understanding of how current practices target and alter healing in the context of

microbial community structure, membership, and function and how the environment influences

these elements can help establish interventions and methods for a more effective preparation.

In addition, a more proactive approach could be used to better maintain an environment

for an anastomosis to heal. Probiotic supplementation with Bifidobacteria and Lactobacilli before

and after surgery have been shown to have possible therapeutic effects (53-54), Combining

probiotics with a fiber rich diet has been shown to decrease the rate of AL, due to the production

of short chain fatty acids (55). Creating a combination of probiotic species and fiber for

consumption before and after the anastomosis creation could prophylactically preserve beneficial

species and provide the sources of energy to keep low abundance pathogens from proliferating

and responding to the often hostile inflammatory environment that occurs after major resection
in a high risk patient. Understanding how surgeons can maintain a more favorable local intestinal

environment during intestinal resection is now scientifically supported by studies that

demonstrate that bacteria “sense” local environmental changes and “respond” with enhanced

virulence via in cell-cell communication systems and quorum sensing (56-57).

Along this line of reasoning, pathogens such as P. aeruginosa and E. faecalis have been

implicated in the pathogenesis of ALs. They have been shown to express virulence traits, such as

collagenase, that can directly impair anastomotic healing leading to leak. Contemporaneous with

this effect, the composition and function of the indigenous microbiome present at anastomotic

tissues becomes highly disrupted and allows these pathogens not only to proliferate, but also to

become “cued” by local environmental factors released during surgery possibly as a result of

tissue manipulation, transient ischemia, and inflammation. As a result of this process, these

pathogens are then activated and equipped to amplify the tissue inflammatory response after

anastomotic surgery, which remains unbalanced as a result of the lack of opposing forces by the

normal microbiota which have been eliminated by antibiotic use. As such, a pathoadaptive

response to normal healing ensues, leading to leak.

Given that bacteria can rapidly evolve within minutes to hours and subvert all attempts to

silence or eliminate them, new approaches are needed. As we have witnessed with the emerging

problem of antibiotic resistance, there are no evolution-proof drugs. Simply targeting the

pathogens and not their virulence factors would leave room for the expansion and expression of

different forms of virulence and other pathogens acquiring the collagenase phenotype either by

horizontal gene transfer or other mechanisms. While many approaches are now being proposed,

such as phage therapy, cas-CRISPR targeted gene editing, and oral antibodies to target virulence

factors, novel approaches that might suppress virulence expression at its very onset may be a
more evolutionarily stable strategy. This approach may allow the normal microbiota to

participate in healing (58). Approaches to consider include the idea that it might bacteria may be

rendered harmless without elimination. Surprisingly this idea was proposed as early as 1899,

before antibiotics and DNA were even discovered (59).

APPLYING MICROBIOME SCIENCE TO CURRENT PRACTICES IN COLORECTAL

SURGERY

Surgeons have long realized the importance of understanding how intestinal microbes

influence outcomes following colorectal surgery. As we enter the molecular era of personalized

medicine driven by advances next generation technology, many of the time-honored practices

that are associated with improved outcomes will be confirmed or rejected at the scientific level.

The bundled approach of ERAS is a great example of this as is the potential benefit of use of

hyperoxygenation during colorectal surgery (60-61). As explained by the above discussion, early

feeding, avoidance of opioids, limiting transient ischemia, and early laxation may all be working

to improve outcomes, in part, via their actions on the intestinal microbiome.

Understanding precisely how the microbiota respond to surgery and the various

manipulations that follow will be critical to design new therapies to improve outcome. For

example, in our own work, we have shown that intestinal phosphate becomes rapidly depleted in

the gut following surgery and is a critical “public good” resource for bacteria to thrive. When

phosphate is depleted, bacteria express virulence in order to gain access to host cells where there

is abundant phosphate such as ATP. In this process, cellular harm occurs. We developed an oral

phosphate based solution that delivers phosphate to the distal gut, suppresses bacterial virulence

without affecting bacterial growth, and prevents AL in mice (62). Properly nourishing the gut

during anastomotic surgery in the future will require approaches that appeal to the viability and
survival of the normal microbiota, which seems to play an underappreciated role in intestinal

healing. Yet not allowing the “bad actors” to proliferate may require non-microbiocidal

approaches given the concern of rapidly evolving antibiotic resistance. Through ERAS and other

approaches, it is now possible for surgeons to apply next generation technology to determine

what works and why. Using this approach, science-based design will lead us forward to improve

outcomes and prevent devastating complications such as ALs and SSIs, to which no surgeon is

immune.
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