Preparing the Bowel (Microbiome) for Surgery: Surgical Bioresilience

Abstract

The preparation of the bowel for radical surgery is a corner stone of elective colorectal practice. The evidence for this intervention is of variable quality and it is often contradictory, yet there is now a global move toward the adoption of oral antibiotic therapy for the reduction of perioperative infective complications, such as surgical site infections. The gut microbiome is a critical mediator of the systemic inflammatory response to surgical injury, wound healing, and perioperative gut function. The loss of critical microbial symbiotic functions caused by bowel preparation and surgery has an adverse impact on surgical outcomes, yet the mechanisms through which this occurs are poorly defined. In this review, the evidence for bowel preparation strategies is critically appraised in the context of the gut microbiome. The impact of antibiotic therapy on the surgical gut microbiome and the importance of the intestinal “resistome” to surgical recovery is described. Data to support the augmentation of the microbiome through diet, probiotic and symbiotic approaches, as well as fecal transplantation are also appraised. Finally, we propose a novel strategy of bowel preparation defined as “ surgical bioresilience ” and define areas or prioritization in this emerging field. This describes the optimization of surgical intestinal homeostasis and core surgical exposome-microbiome interactions that regulate the wound immune microenvironment, the systemic inflammatory response to surgical injury, and gut function across the perioperative time course.

The objective of modern bowel preparation strategies is to destroy this evolutionary symbiosis, and therefore to reduce the likelihood of direct or indirect pathobiont contamination of wounds that are thought to drive surgical site infections (SSIs) or complications of surgery such as anastomotic leak. Despite half a century of trials, there is a complete absence of mechanistic data to explain how bowel preparation exerts its potential benefit; To date no surgical randomized control trial (RCT) of bowel preparation in humans has studied its impact on intestinal homeostasis across the perioperative time course or established the functional consequences of these approaches on the surgical microbiome and their secondary functions. This is in part because of the challenges in interpreting the complexity of this highly individualized dynamic system. The result is that we still lack a standard model of the intestinal microbiome response to elective surgical injury that can be selectively targeted by perioperative bowel preparation strategies.

In this review, we outline the current evidence for all forms of bowel preparation, and we assess this in the context of the new science of the gut microbiome. We appraise novel strategies for engineering the surgical exposome and microbiome for improving surgical outcomes and we propose a novel framework for next generation personalized bowel preparation that we refer to as “surgical bioresilience.”

Mechanical Bowel Preparation

In 2011, a Cochrane review of 5,805 patients concluded that there was no evidence for the benefit of mechanical bowel prep alone in colonic resections although it suggested a possible role for selective use in rectal surgery. ¹ Despite this, it is still widely used in practice. Mechanical bowel preparation typically contains a low dose (2 L) polyethylene glycol (PEG) supplemented with electrolytes. This induces an osmotic pull of fluids into the gut causing diarrhea. PEG is toxic to some microbes because it changes the pH and the oxygen content of the colon, and it deprives mutualistic microbes of nutrition. The steady-state growth rate of several species also decreases as the environmental osmolality is increased, ² preventing the growth of commensal strains in vitro. ³ The combination of these mechanical and physiological perturbations decimates the anaerobic colonic ecosystem. ⁴

A study of 23 healthy individuals given PEG demonstrated dramatic but short lasting changes in colonic diversity of the gut microbiome, with a 34.7-fold reduction in the total number of bacteria, when compared with the fecal samples at baseline. ⁵ The numbers of methanogenic archaea per gram of feces also experienced a 20-fold reduction in their total number, although levels of both bacteria and archaea were restored to baseline levels between 14 and 28 days. However, significant dose response was also observed. Those subjects given a single 2 L dose of PEG demonstrated an expansion in less prevalent gut bacteria, including several facultative aerobes such as Fusobacteria, Proteobacteria, and Dorea formicigenerans , typically bacteria associated with inflammatory intestinal states and which are potentially suboptimal for intestinal healing. Interestingly, two separate dosages of purgative introduced fewer alterations to the intestinal microbiota and resulted in a colon with a lower bacterial load than the single dose. The authors also noted an increase in the intestinal fecal serine proteases, which also has implications for wound healing. ⁶

Quantitative imaging studies in mice challenged with PEG have demonstrated reciprocal changes in the loss of microbiome diversity and the destruction of the mucus barrier. ³ A reduction of the mucus-consuming bacterium Akkermansia muciniphila was strongly linked to a decrease in mucin glycoside hydrolase expression supporting the concept that microbiota-driven feedback mechanism influences mucosal resistance. The destruction of the gut barrier also had significant implications for the immune response which exhibited temporary changes in cytokine expression; although the mucosa and microbiome populations eventually recovered after PEG treatment, a lasting immunoglobulin G response against commensal bacteria remained. ³ In surgical practice, however, mechanical bowel preparation strategies are seldom given in isolation.

Mechanical Bowel Preparation with Oral Antibiotics

Despite this level of evidence, there is still no consensus between guidelines in the United States, ⁷ Europe, ⁸ and Asia Pacific ⁹ on the precise use of both mechanical bowel prep and oral antibiotics (MBPOA) in preparation of patients for colorectal surgery. Multiple retrospective analyses of the National Surgical Quality Improvement Program registry, have found that patients who receive MBPOA are at a significantly decreased risk of developing ileus, SSI, organ space infection, length of stay, wound dehiscence, and anastomotic leak compared with those who received no preparation. ¹⁰ Despite these data, RCTs have been heterogeneous and difficult to interpret, largely because of the inconsistency of the comparator group. For example, analyses of OA have compared their effectiveness against intravenous antibiotics alone, ¹¹ or studied them in combination with mechanical bowel preparation and compared them to MBP ¹¹ or no MBP, respectively. ¹² Many early trials were also of poor quality and recruited heterogeneous patient cohorts with both benign and malignant disease undergoing both open and minimally invasive surgical procedures ( Table 1 ).

Table 1. Randomized controlled trials of oral antibiotic use in conjunction with mechanical bowel preparation and intravenous antibiotics.

Author	Type	Intervention	Number	Population	Oral antibiotics	IV antibiotics	Dosing	Laparoscopic	ERAS	Adverse events or side effects	Bowel prep controlled	Jadad score	SSI treatment / control (%)	Leak treatment / control (%)
Takesue et al 2000 56	Single-center RCT	Oral abx vs. mechanical bowel preparation (MBP)	83	Elective colorectal cancer	Kanamycin and metronidazole	Cefmetazol	3 dose night prior to surgery	Yes/No	No	MRSA	Yes	1	13.1 / 17.8% ns	5.3 / 4.4% ns
Ishida et al 2001 57	Single-center RCT	Oral abx + MBP vs. MBP	143	Elective colorectal disease	Kanamycin and erythromycin	Cefotiam	2 days prior to surgery	No	No	MRSA	Yes	3	11 / 24% p  = 0.04 a	1.4 / 2.8% ns
Lewis 2002 58	Single-center RCT	Oral vs. IV abx	215	Elective colorectal cancer	Neomycin and metronidazole	Amikacin and metronidazole	1 day preop	No	No	No	No	3	17 / 5% p  < 0.01 a	1 / 2.5% ns
Espin-Basany et al 2005 59	Single-center RCT	Oral abx vs. MBP	300	Elective colorectal disease	Neomycin and metronidazole	Cefoxitin	1 day prior to surgery	No	No	N + V and pain	Yes	2	7 / 8 / 6% ns	2 / 2 / 3% ns
Kobayashi et al 2007 60	Multicenter RCT	Oral + IV vs. IV abx	491	Elective colorectal cancer	Kanamycin and erythromycin	Cefmetazol	1 day preop	Yes/No	No	No	No	3	7 / 10.7% ns	Not reported
Roos et al 2011 61	Single-center RCT	Oral + IV vs. IV abx	289	Elective GI (upper and lower)	Polymyxin B sulfate tobramycin amphotericin	Cefuroxime and metronidazole	Pre 2 days and 3 days postop	Yes/No	No	No	No	5	19.6 / 30.8% p  = 0.02 a	6.3 / 15.1% p  = 0.01 a
Ikeda et al 2016 62	Single-center RCT	Oral + IV vs. IV abx	511	Elective lap colorectal stratified for chemoradiation, type II DM	Metronidazole and kanamycin	Cefmetazol	1 dose night prior to surgery	Yes	No	No	Yes	3	7.8 / 7.8% ns	1.2 / 2.5% ns
Hata et al 2016 63	Multicenter RCT	Oral + IV vs. IV abx	579	Elective laparoscopic colorectal cancer	Kanamycin and metronidazole	Cefmetazol	2 doses day prior to surgery	Yes	No	No	Yes	3	7.3 v/12.8% ns	1.7 / 2% ns
Anjum et al 2017 64	Single-center RCT	Oral abx + MBP vs. MBP	95	Scheduled abdominal surgery	Metronidazole and levofloxacin	Cephalosporin and metronidazole	Day before surgery	Yes/No	No	No	Yes	3	8.4 / 27.3% p  = 0.001 a	Not reported
Oshima et al 2013 11	RCT	Oral + IV vs. IV abx	200	UC	Kanamycin and metronidazole	Flomoxef	Day before surgery	No	No	No	Yes	3	6.2 / 22.4% p  = 0.001 a	Not reported
Koskenvuo et al 2019 13	Multicenter RCT	Oral abx + MBP vs. no prep	396	Elective colectomy	Neomycin and metronidazole	Cefuroxime and metronidazole	Day before surgery	Yes/No	Yes	No	Yes	3	7 / 11% ns	4 / 4% ns
Espin Basany 2020 14	Multicenter RCT	Oral vs. no oral abx	565	Elective colorectal disease	Ciprofloxacin and metronidazole	Cefuroxime and metronidazole	Day before surgery	Yes/No	No	No	n/a	3	5 / 11% p  = 0.013 a	Not reported

Abbreviations: abx, antibiotics; DM, diabetes mellitus; ERAS, enhanced recovery after surgery; GI, gastrointestinal; IV, intravenous; MBP, mechanical bowel preparation; MRSA, methicillin-resistant Staphylococcus aureus; ns, not significant; RCT, randomized control trial; SSI, surgical site infection; UC, ulcerative colitis.

^a Statistical significance of p ≤ 0.05.

More recent, higher quality RCTs are beginning to provide more robust data. For example, the MOBILE trial was a multicenter, parallel, single-blinded trial of patients undergoing colonic resection, who were randomly assigned (1:1) to either mechanical and OA bowel preparation (MOABP) or no bowel preparation (NBP) in four hospitals in Finland. This found no difference between MOABP and NBP among patients undergoing colon resection in terms of SSIs or overall morbidity. ¹³ The ORALEV trial was a multicenter, pragmatic, RCT of patients undergoing colonic surgery in five major hospitals in Spain. This did find a significant reduction in SSI rates in those receiving OA comparing to patients not receiving OA, and no MBP was used. ¹⁴

Despite the challenges of trial heterogeneity, a recent networked meta-analysis of RCTs comparing methods of bowel preparation that only included studies using good aerobic and anaerobic antibiotic cover in all groups demonstrated that the addition of OA to intravenous reduced the incidence of SSI by more than 50%. This was the case both with and without the use of MBP, although there were minimal differences between treatments in anastomotic leak rates or in any of the secondary outcomes. ¹⁵

When considered through the prism of the gut microbiome more significant mechanistic challenges exist. For example, many MBPOA studies have conflated colonic and rectal surgery, which are subject to major variations in the surgical environmental stressors on the microbiome. Surgical techniques and the use of diversion stomas vary in these cohorts as do surgical outcomes, but so do the use of neoadjuvant therapies, particularly radiotherapy which also fundamentally alters the microbiome. ¹⁶ Moreover, the ecology of the microbiomes in the left and right colon vary, as do the colonic and rectal ecosystems. ¹⁷ Second, because the luminal and mucosal microbiomes play a critical role in the development of both benign and malignant disease, and the underlying surgical pathology creates further variation in microbial ecology and functions. If nothing else, patients with inflammatory diseases of the colon are more likely to have been previously exposed to antibiotics. Finally, the microbiome is profoundly influenced by both prehabilitation and enhanced recovery strategies, because these influence the use of drugs (e.g., analgesics), diet, nasogastric tubes, and surgical drainage. Very few trials have accounted for the impact of these important variables on the efficacy and toxicity of the preparation strategy ( Table 1 ).

Antibiotic-Associated Perturbations of the Microbiome

Perioperative antibiotics have the potential to disrupt every aspect of the gut microbiome, both in terms of the absolute number of bacteria, relative proportions of bacteria, the functions of those networks of bacteria, their rate of gene transfer, co-metabolism, and general symbiotic functions. A short course of an oral penicillin will typically exert a mild but significant reduction in microbial diversity. In most cases, our microbiomes will have enough plasticity to grow back into its pretreatment structure after a few weeks. However, broad-spectrum antibiotics have a much more profound influence. In one randomized study of 22 humans, those taking a 5-day oral cocktail of neomycin, vancomycin, and metronidazole caused a 10,000-fold reduction in gut bacterial load, and a change in diversity that in some cases lasted more than 6 months. ¹⁸ In those individuals who do not have a resilient microbiome, it may never return to its pretreatment composition, diversity, or function and the gut microbiome demonstrates “antibiotic scarring.” Some individuals are susceptible to this more than others, and in one longitudinal study of a single dose of azithromycin demonstrated similar gut diversity to patient who had been cared for on intensive care. ¹⁸

After broad-spectrum antibiotics, the relative abundance of Firmicutes and Actinobacteria phyla typically fall, and in particular the genus Bifidobacterium . The Bacteroidetes and phylum may, however, benefit, in part because Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones. ¹⁹ In some cases, particular resistant species will explode into a massive bloom.

Antibiotic use also exerts physiological stress on the host. For example, they modify metabolism by disrupting gut homeostasis and luminal signaling even when the diversity remains stable. In mice models, antibiotic-induced loss of luminal Firmicutes and Bacteroidetes species decreases baseline serum glucose levels, reduces glucose surge in a tolerance test, and improves insulin sensitivity without altering adiposity. This is because they influence the cecal gene expression of glucagon-like peptide-1 possibly caused by a shift in colonocyte energy utilization from short-chain fatty acids (SCFAs) to glucose. ²⁰

Microbiota-associated metabolites such as SCFAs, bile acids, amino acids, and tryptophan metabolites all have a critical role in mediating intestinal homeostasis ^{21 22} as have medium- (MCFAs) and long-chain fatty acids (LCFAs). MCFAs are quickly absorbed and stimulate cell renewal and repair of the gut epithelium, ²³ whereas LCFAs can modulate intestinal damage. ²⁴ Therefore, disruption of nutritional interventions that optimize these co-metabolic pathways are of great importance, and antibiotics are extremely disruptive in this regard. A western diet (WD) high in fat not only influences the efficacy of antibiotics, such as ciprofloxacin, ²⁵ but antibiotics also impair epithelial mitochondrial dysfunction caused by a high fat diet, driving the expansion of Enterobacteriaceae that in turn exacerbates mucosal inflammation. ²⁶

The U.K. government calculates that by conservative estimates, antibiotic resistance will cause 10 million deaths globally by 2050 at a cost of £66 trillion. ²⁷ Data from the Centers for Disease Control and Prevention's National Healthcare Safety Network encompassing 288,458 colorectal surgery procedures found that 43% of SSIs are caused by pathogens resistant to standard prophylactic antibiotics (cefazolin and metronidazole), suggesting that current perioperative protocols may be inadequate for prophylaxis. The authors go on to predict that another 30% reduction in efficacy of antibiotic prophylaxis would result in an additional 4,586 deaths within the colorectal surgery population per year in the United States. The intestinal resistome is a biomarker of failure and health inequality, and the fact that we are now officially in the postantibiotic era makes the widespread adoption of OA as surgical policy problematic; at best, this practice runs contrary to the principles of effective antibiotic stewardship.

Surgical Scarring of the Microbiome

Collectively therefore, perioperative medication, starvation, inadequate nutrition, MBPOA, and surgery itself creates a mass extinction event in the gut. ²⁸ This “great dying” has a lasting impact on the gut microbiome and some patients are unable to return to their preoperative intestinal ecology. Studies in patients undergoing colorectal surgery suggest this effect is greatly enhanced in those patients who suffer complications and repeated antibiotic treatment. ²⁹ This surgical scarring of the microbiome is hugely significant, not just in terms of postoperative intestinal motility, and gut function, but also in the development of low anterior resection syndrome because diet-microbiome interactions have a reciprocal relationship with gut motility. ³⁰ More problematically surgical scarring of the microbiome also fundamentally influences how patients metabolize drugs with immediate implications for perioperative pain control. For example, the microbiome is in part responsible for the bioavailability of acetaminophen ³¹ and opiates. ³² There are also longer-term implications for patients with surgical microbiome scarring because gut microbes influence both the efficacy and toxicity of adjuvant cytotoxic chemotherapies and immunotherapies. ³³ A “healthy” postoperative microbiome is therefore imperative for a quality of life after surgery and survival from malignant disease.

Perioperative Diet-Microbiome Interactions

Forty to 50% of patients with gastrointestinal cancer surgery are malnourished at the time of surgery. ³⁴ Perioperative nutrition is now a core pillar of modern enhanced recovery after surgery programs, which typically employ a carbohydrate loading strategy for mitigating surgically induced insulin resistance (IR). The evidence for this intervention is not without its controversy. A networked meta-analysis of 43 trials involving 3,110 participants compared fasting, preoperative low-dose and high-dose carbohydrate administration decreased postoperative length of stay by just 0.4 (95% confidence interval 0.03–0.7) and 0.2 (0.04–0.4) days, respectively. ³⁵ There was no significant decrease in length of stay compared with water or placebo, or in the postoperative complication rate between carbohydrate and control groups. This is in some respects unsurprising given the importance of the microbiome to insulin sensitivity, intestinal permeability, immune cell trafficking, and intestinal hormone availability. Indeed, there is increasing evidence that the microbiome can be leveraged to create personalized diets for the precision regulation of IR and blood sugar. ³⁶

A WD, that is high in fat and animal protein and low in fiber is proinflammatory, and therefore adversely influences our response to surgical injury. Dietary fibers are defined as a diverse set of plant-based carbohydrates that are neither digested nor absorbed in the small intestine and they have a degree of polymerization of three or more monomeric units, plus lignin. ³⁷ Fibers vary in their chemistry, and pattern of viscosity and some fibers act as prebiotics, because they are fermented by bacteria into anti-inflammatory SCFAs that fuel colonocytes. In practice, microbes metabolize fiber through a mutualistic network, known as cross-feeding through a shared number of enzymes and fiber metabolism. Mucosal epithelial species within the phylum Firmicutes (e.g., Faecalibacterium prausnitzii ) produce SCFAs from fibers which have anti-inflammatory, wound healing properties.

The importance of diet and low fiber intake to postoperative outcomes has recently been demonstrated in a study of mice randomized to standard chow (SD; low fat, high fiber) or a WD (high fat, low fiber), administered for 6 weeks prior to an open colonic anastomosis model with intravenous antibiotics at induction. Mice on a WD had a significantly increased anastomotic leak rate, and experienced a dramatic loss of microbial biodiversity preoperatively, which corresponded to decreased Bacteroidetes and increased Enterococcus compared with the SD-fed cohort. ³⁸ This trend continued postoperatively, where collagenase producing Enterococcus comprised 65 to 90% of the microbiota in the first postoperative week in WD, compared with 4 to 15% in SD mice. The disturbance in microbiota triggered by surgery in both groups was pronounced, but returned to preoperative composition much earlier in SD versus WD fed mice (2 vs. 4 weeks, respectively). Switching the diets just 2 days prior to surgery, attenuated the WD-induced diversity depletion of the colonic microbiota composition and maintained the abundance of Bacteroidetes, decreased abundance of Enterococcus preoperatively. Importantly, the dietary switch to SD preoperatively was also associated with reduced anastomotic leak rate; this protective effect was unaffected by a postoperative return to WD.

Pre-, Pro-, and Synbiotics

Probiotic and prebiotic strategies have been extensively trialed in elective colorectal surgery. ³⁹ However, major challenges also remain in the robust interpretation of these data ( Supplementary Table S1 , online only). For example, protocols vary widely between studies both in terms of strains, dose, and duration, as well as in the confounding variables of mechanical bowel preparation, OA and intravenous antibiotics. Despite this, two recent meta-analyses have suggested that probiotics reduce the risk of infective complications of colorectal cancer surgery. Encompassing 1,566 patients taken from 14 RCTs, Chen et al reported a 37% reduction in overall postoperative infection risk in patients taking perioperative probiotics when compared with those receiving placebo or standard care; this benefit remained (18%) after accounting for publication bias. ⁴⁰ Moreover, probiotics significantly reduced rates of SSI, pneumonia, urinary infection, and diarrhea. In a similar meta-analysis encompassing 11 RCTs, significant benefits of probiotics were reported across the postoperative domains of: septicemia, infection, diarrhea, length of stay, return to normal gut function, and days of antibiotic use. ⁴¹ It should be noted, however, that not all studies reported the same endpoints (for example, only 4 of 11 gave data on return to normal gut function and first defecation) or used the same definitions for SSI ( Supplementary Table S2 , online only).

A greater challenge with these studies is that very few demonstrate a mechanism of action. Komatsu et al observed probiotics ( Lactobacillus casei and Bifidobacterium breve ) were detectable in fecal samples from treated patients and at 7 days postoperatively and are therefore likely to have a dose effect. ⁴² Where molecular mechanisms have been studied, these have largely demonstrated improved barrier function (e.g., Bifidobacterium infantis ) ⁴³ or changes in circulating cytokine functions. ⁴⁴ Despite this, probiotic technologies are evolving rapidly toward synthetically engineered “live biotherapeutics.” Next-generation probiotics are a class of organisms developed exclusively for pharmaceutical application and many strains have typically been identified from clinical trials. Live biotherapeutic product (LBP) can therefore be targeted toward host immunology or pathogenic drivers of clinical relevance. ⁴⁵ Well-powered, robust probiotic trials of LBP species such as Akkermansia muciniphila may have significant potential in this regard, and they should be prioritized in trials for optimizing surgical gut health.

Fecal Microbiome Transplantation

Fecal microbiome transplantation (FMT) entails the transplantation of healthy screened donor feces into a recipient. This procedure transplants the entire microbiome and by doing so, it is hypothesized to restore the microbiota composition and the gut homeostasis. FMT is widely accepted as a treatment for recurrent Clostridioides difficile (rCDI) infections with success rates as high as 90%. ^{46 47} Due to this great success in rCDI, FMT as a therapeutic treatment for other disorders such as inflammatory bowel diseases, and particularly ulcerative colitis (UC), are gaining interest. At the time of writing this protocol there are even 16 active clinical trials investigating FMT as a treatment for UC. ⁴⁸ Recent data also suggests this is an effective method for regulating IR in obesity ⁴⁹ and for managing the long-term symptoms of irritable bowel syndrome. ⁵⁰ Yet, no trials to date have been performed in elective colorectal surgery, either to prepare the bowel or to reconstitute the microbiome after the completion of surgery. It is generally accepted that for an FMT to be successful, the FMT product must match the in vivo product of the donor as closely as possible. It is tempting to hypothesize, therefore, that it is possible to transplant the fecal microbiome of a “healing phenotype” into a patient of high risk of SSI or anastomotic leak, based on a preoperative measure of their microbiome. Trials in this field are now urgently needed.

Surgical Bioresilience

More modern approaches to bowel preparation have been proposed that account for the microbiome, such as “Bowel Preparation 2.0.” ⁵¹ The aim is to promote intestinal diversity and suppress blooms of pathobionts through the judicious optimization of diet-microbiome interactions, and selective targeting of pathogens. However, a definition of the ideal bowel preparation strategy is required that can guide future surgical research and trials. Here, we propose that the ideal microbiome-enhanced bowel preparation strategy should meet the following standards:

• (1) The promotion of an individual's intestinal biodiversity, as a global measure of surgical gut health.

• (2) Prevention of antimicrobial resistance.

• (3) The selective inhibition of pathobiont populations and their functions that drive SSI and anastomotic leak.

• (4) The maintenance of intestinal homeostasis (and the health of the gut barrier) for an optimal immune response to surgical trauma.

• (5) Optimization of gut microbial co-metabolism and the enzymatic functions of the microbiome necessary for safe drug and chemotherapy metabolism.

• (6) Enhanced microbiome-diet network interactions for perioperative nutrition, wound healing, gut function, and quality of life.

These objectives should exist along the continuum of the patient surgical journey and they can be summarized through the concept of surgical bioresilience ( Fig. 1 ). This also requires quantifiable measure of the modifiable environmental stresses that are placed on the microbiome during surgery, and the resulting impact of exposome-microbiome interactions on the wound microenvironment and broader gut functions. Collectively, patient-specific and environmental stresses on the microbiome can be considered as the “surgical exposome.” This concept incorporates both the hospital microbiome and the surgical technique, which in colorectal surgery inevitably includes the excision of part or indeed all of the colon and the microbes that reside within.

Fig. 1.

A new model for the preparation of the gut based on the theory of surgical bioresilience. This describes a continuation of steps necessary for the continuous ecological and functional optimization of the gut microbiome for optimal intestinal homeostasis, wound healing, and the competitive inhibition of pathobionts across the entire operative journey. It will leverage advances in synthetic biology to engineer highly targeted strains of bacteria for targeting surgical pathogens through vaccination, next-generation live biotherapeutic product (LBP), and phage therapy.

Advances in synthetic biology are now providing us with a novel set of tools through which the microbiome may be engineered for improved surgical outcomes. Phage are increasingly being used, for example, for the successful treatment of multidrug resistant surgical wound infections such as Acinetobacter baumannii and Klebsiella pneumoniae . ⁵² Antibiofilm phage cocktails have also been developed with a broad host range against Escherichia coli strains isolated from urine. ⁵³ Advances in CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technologies and messenger ribonucleic acid vaccine technologies are also heralding a new dawn in precision antiviral and antimicrobial vaccines, and they are being leveraged to create therapeutic vaccines for cancer. ⁵⁴ It is now at last conceivable that emerging vaccination technologies being developed against common surgical pathogens responsible for SSI, such as Staphylococcus aureus , ⁵⁵ will finally become a reality.

Conclusion

The clinical evidence for current approaches to the preparation of the bowel for colorectal surgery is conflicting. A major reason for this is that they have not accounted for the importance of the gut microbiome in determining their safety or efficacy. Our intestinal microbes represent a critical target through which novel, highly personalized methods for improving the bioresilience of the gut to surgical injury can be developed. Clinical trials of plant-based and personalized diets, LBPs, and FMT are urgently needed to deliver on this vision and to support their wider adoption. The true promise of the gut microbiome in colorectal surgery, however, is more likely to be based on a targeted engineering of wound immune microenvironments for optimized wound healing, gut function, and therapeutic benefit.