Rationale for Colonic Pre-Habilitation Prior to Restoration of Gastrointestinal Continuity

Abstract

The emergence of the gut microbiome as a complex ecosystem that plays a key role in human heath and disease has touched virtually every aspect of medical and surgical care. With the advent of next-generation technology to interrogate the microbiome at the level of its membership, community structure and production of metabolites, applying measures by which the gut microbiome can be manipulated to the advantage of both the patient and provider is now possible. Among the many proposed methods, the most practical and promising is dietary pre-habilitation of the gut microbiome prior to high-risk anastomotic surgery. In this review, we will outline the scientific rationale and molecular underpinning that support dietary pre-habilitation as a practical and deliverable method to prevent complications after high-risk anastomotic surgery.

Patients in whom high-risk intestinal surgery is being proposed often undergo a complex series of tests and neoadjuvant therapy prior to the actual procedure. This may include a biopsy, multiple imaging tests, neoadjuvant chemoradiotherapy in the case of cancer, enterostomal therapy when contemplating reversal of a stoma or an ileostomy, etc. In many cases such as after a colon polyp removal, antibiotic agents are administered putting the microbiome at risk, but also the cancer itself can alter or be altered by the microbiome.¹ In addition, bowel preparation with purgative cleansing agents can also alter the microbiome.² Chemoradiotherapy applied either in the pre-operative or post-operative period has a profound effect on the gut microbiota and can allow the proliferation and predominance of highly resistant and virulence pathogens to colonize the gut including extended-spectrum β-lactamase (ESBL)-producing Escherichia coli strains, Pseudomonas aeruginosa, Serratia marcescens, and Enteroccoccus faecalis.³ Finally, periods of starvation, extreme psychological and physiologic stress, use of biologic agents, and substance abuse often complicate high risk gastrointestinal surgery.⁴

In the aggregate, these findings suggest that many patients facing high-risk anastomotic surgery, (stoma closure, segmental resection, total colectomy) suffer from a grossly abnormal microbiome colonized by highly virulent and antimicrobial-resistant (AMR) microbiota. Therefore, the extent to which these potential pathogens can be identified prior to surgery and either be eliminated or contained through the course of surgery is relevant. This may be especially relevant given that today, under current asepsis protocol, most pathogens that cause life-threatening post-operative infections (deep wound infections, prosthetic infections, anastomotic leaks, etc.) originate from the gut microbiome.⁵

Definition of the Gut Microbiome

The gut microbiome is most commonly reflected in either an expelled stool sample or a rectal swab. Yet the gastrointestinal tract comprises a microbiota that spans its entire regional and spatial trajectory including the mouth, esophagus, stomach, small bowel, and colon. Spatially there are distinct microbiomes in the lumen, mucus layer, on the epithelium and within the crypts.⁶ Yet as a matter of routine and practicality, expelled stool and rectal swabs are used to interrogate the microbiome, although some controversy exits in the sampling method.⁷ Nonetheless, once a sample is procured and its timing is synchronized across comparator groups, the microbiome consists of the taxa present, the relative abundance of each to each other, the genes they carry identified by specific probes, and the metabolites they produce. Hence the comprehensive description of the microbiome including its membership, community structure, relative abundance, evenness, its diversity, and its function (i.e., proteins/metabolites).⁸ Therefore the term microbiome can encompass various aspects of an interrogated sample depending on how it is analyzed either by 16s rRNA genetic sequencing, probing by polymerase chain reaction (PCR) for specific AMR genes, metagenomics, metatranscriptomics, proteomics, or metabolomics. Often a multi0omics approach is used, and various techniques are applied.

A major limitation of genetic/metabolomics analytics is that although terabytes of data are generated and associations can be made, causation to a given disease state or phenotype in humans remains a major challenge. In animals expressing a particular phenotype of interest, fecal transfer to a germ-free mouse can define the putative role of the microbiome assembly to the phenotype. Although in humans, this approach is challenging, studies in monozygotic twins discordant for multiple sclerosis have demonstrated that fecal transfer from the affected twin to germ-free mice recapitulated the disease phenotype.⁹ Only in this manner can causation of a phenotype be connected to a given microbiome. Terms such as “linked to” and “correlated with” unfortunately seem to suggest that association can infer causation. For example, were a specific dietary intervention during the pre-operative period (i.e., dietary pre-habilitation) to change the microbiome such that a group of test subjects demonstrated a greater rate of anastomotic healing (i.e., fewer leaks), then to prove causation between the microbiome and the decreased anastomotic leak rate would require transfer of the whole stool microbiota from the test subjects to germ-free mice undergoing anastomotic surgery. These mice would then need to demonstrate improved anastomotic healing compared with those transferred stool from control subjects not subjected to dietary pre-habilitation and whose microbiome analysis was demonstrated to differ from those undergoing dietary pre-habilitation. Only under such rigorous experimental conditions can one prove causation of diet to anastomotic healing in humans. That said, there is compelling causal inference in this field that a diet to microbiome to anastomotic healing connection is operative and can be leveraged to the advantage of both surgeon and patient.^10–12

A Brief History of the Role of the Gut Microbiome in Anastomotic Leak Etiology and Pathogenesis

Compelling evidence from as early as 1955, confirmed in 1976 and 1985, re-confirmed in 1994, and then mechanistically elucidated in 2015 has provided rigorous proof that intestinal bacteria alone are sufficient to cause an anastomotic leak.^13–17 The fact that oral antibiotic agents are the mainstay of surgical site infection (SSI) prevention inclusive of anastomotic leak and that selective use of a protective stoma in low colorectal surgery still is recommended, speaks to the notion that even in the best of hands, anastomotic leaks still occur and that microbes are involved.¹⁸ We have confirmed a role for gut microbes in anastomotic leak etiology and pathogenesis by demonstrating in animals that intestinal bacteria expressing the tissue destroying enzyme collagenase, can cause anastomotic leak.¹⁷ In humans we demonstrated that humans with anastomotic leaks harbors a predominance of collagenase-producing bacteria in the gut and that transfer of microbes present at anastomotic leak sites to the mouse gut can independently cause an anastomotic leak.^19,20 In the aggregate these data provide a compelling case that microbes can complicate anastomotic healing such that elimination or virulence suppression of the offending pathogens (i.e., Pseudomonas aeruginosa, Entercoccus faecalis, Serratia marcescens, and others) while preserving those microbiota that normally suppress their proliferation (i.e., the normal commensal microbiota). Yet today, the practice of indiscriminate killing of as many gut microbes as possible with broad-spectrum antibiotic agents, seems anathema to the growing problem of antimicrobial resistance (AMR). In fact, as many as 50% of patients with an SSI culture positive for an AMR pathogen. This disturbing trend needs to be addressed and alternative approaches proposed.²¹

Can Dietary Pre-Habilitation Prevent Anastomotic Leak in High-Risk Patients and is it a More Evolutionarily Stable Strategy Than Escalating the Use of Antibiotic Agents?

Today, patients presenting for stoma reversal, primary segmental resection, or total abdominal colectomy with ileal pouch reconstruction harbor complex microbiology. Many of these patients have been exposed to major trauma, physiologic and psychological stress, antibiotic agents, biopsies, neoadjuvant chemoradiotherapy in the case of cancer, and biologic agents in the case of patients with inflammatory bowel disease. As a result, the type of microbes they harbor at potential sites of a proposed anastomotic connection is likely to be highly abnormal and characterized by highly virulent, antimicrobial resistant health-care–associated pathogens. Many of the most common pathogens present at these sites (i.e., Pseudomonas aeruginosa, Enterococcus faecalis) are also those that express the highest rate of the tissue-destroying enzyme collagenase and are resistant to the most common antibiotic agents chosen for prophylaxis.²² In fact, the most common pathogens present at anastomotic leak sites are Pseudomonas aeruginosa and Enterococcus faecalis.²² Although many will assume these pathogens are a consequence of a leak not the cause of it, work from our laboratory and elsewhere suggests otherwise.

Despite programs designed at antibiotic stewardship to limit the use of antibiotic agents, there is a disturbing trend in surgery to administer more powerful and broader spectrum antibiotic agents as countermeasure to rising rates of SSIs. This practice is most prevalent in procedures at highest risk for an SSI, namely pancreaticoduodenectomy²³ and colorectal surgery.²⁴ Surgical site infection rates, inclusive of anastomotic leak rates, can be as high as 15% to 20% in these cases. The trend in the literature is to apply broader and more powerful antibiotic agents in such cases. Unfortunately this approach is not sustainable as we consider what others are predicting to be the next pandemic: an increase in AMR pathogen-related deaths after elective surgery.²⁵

An emerging trend in SSI prevention is to survey one's gut microbiome pre-operatively to pre-emptively address the potential to cause post-operative infection-related complications. In fact, today, under mandated asepsis protocols, most pathogens associated with SSIs are gut derived. Through a Trojan horse mechanisms of infection, pathogens present in the gut can find their way to a wound by silently traveling inside an immune cell that ends up in the wound site.^12,26–29 Given that wounds are chemoattractants for immune cells, those carrying a pathogen are potentially infectious vectors. This mechanism can be operative at an anastomotic wound or at a remote site such as a hip prosthesis.²⁹ Given this route of infection pathogenesis, a more complete analysis of the gut microbiome and its role in SSI occurrence, course, and outcome is needed.

Among all methods to durably modulate the microbiome, including the use of antibiotic agents, probiotics, prebiotics, fecal transplants, etc., diet remains as not only the most effective, but also the most sustainable.^30,31 Diet composition is among the most powerful influences on one's microbiome. Remarkably, decades of a poor dietary history can be changed to alter the microbiome in a matter of 24 hours. For example, consumption of a Western diet is associated with colonization of AMR pathogens,¹⁰ a predominance of collagenolytic pathogens,¹¹ and a high risk for SSI development.^32,33 Yet experimental studies suggest that this can be reversed in terms of its risk on the microbiome and SSIs, within 48 hours of a dietary change.^11,33 Decades of work by the Flint Laboratory in Scotland has demonstrated the malleability of the human gut microbiome via short-term dietary change.³⁴ It thus seems reasonable to conclude that dietary pre-habilitation of the gut microbiome can contain the presence and effect of highly pathogenic, virulent, and resistant organism in the gut whose properties can complicate anastomotic healing and cause an deep SSI in high-risk patients.

The Role of Diet on the Presence and Elimination of AMR Genes in Microbes Present in the Gut of High-Risk Surgical Patients

Although obesity, poor diet, and prior healthcare encounter are certainly well-recognized risk factors for anastomotic leak and SSIs,^35,36 it is important to recognize that risk factors are probabilistic measures of complications not deterministic of them. For example, obesity and prior healthcare encounters could increase the relative risk of an SSI to 30% (non-obese patients for argument's sake being approximately 10%). Yet still 70% of patients with these same risk factors (i.e., the majority) do not develop SSIs, thus within-group analyses fail to identify which patients within the group with high-risk factors develop SSIs versus those who do not.³⁷ Interestingly obese patients, who make poor dietary choices and who have been subjected to prior antibiotic exposure, all harbor an altered gut microbiome. Perhaps within-group differences in SSI rates among those with increased risk factors could be distinguished by the microbiome they harbor?³⁸ This latter question then begs a second question of whether pre-operative dietary pre-habilitation can shift the microbiome toward a more normal state such that it suppresses the proliferation of SSI-related pathogens and clears the gut of high-resistant AMR-related pathogens. One can thus imagine a diet-mediated regulation of the gut microbiome as a pre-operative method to decrease the rate of SSIs arising from Trojan horse mechanisms and to decrease the rate of anastomotic leaks.

The Evidence That Diet Alone Can Alter the Gut Microbiome, Suppress its Resistome, and Alter the Outcome from Surgery

Converging lines of evidence now suggest that consumption of a high-fat, low-fiber Western-type diet not only enriches the gut with collagenase-producing bacteria, but also with AMR bacteria.^11,12,39 In addition, consumption of a high-fat, low-fiber Western-type diet is associated with a high rate of SSIs,^40,41 inclusive of anastomotic leaks. Finally, poor outcome after colorectal surgery in terms of cancer recurrence is a function of dietary consumption both before and after surgery. Although reports are emerging that dietary modulation can rid the gut of AMR-related pathogens,¹⁰ whether this results in a real and verifiable decrease in post-operative infection-related complications will require continued study.

There is a pressing need to determine if microbiome modulation can rid the gut of pathogens that can complicate post-operative recovery when faced with a patient at high risk for complications.^42,43 Work in this field has already begun with high-risk procedures such as bone marrow or stem cell transplantation.^44,45 Here we argue that dietary pre-habilitation should begin with consultation of a registered dietician, who then, based on a history and comprehensive examination of all data, generates a prescriptive approach to improving one's diet by consuming foodstuff rich in fiber and low in fat.

As mentioned above, of patients presenting for reconstruction of gastrointestinal continuity, be it to close a protective stoma after abdominal trauma, a segmental resection for cancer, or a restorative proctocolectomy for inflammatory bowel disease, many if not most have been exposed to a prior health care encounter,⁴⁶ a biologic agent, or multiple courses of antibiotic agents. They also have underlying illnesses that can affect their microbiome.^1,47 Finally, in preparation for surgery they often are exposed to purgative cleansing and oral antibiotic agents as part of their bowel preparation. Finally, the psychologic stress the night before surgery when considering the risk of infection, anastomotic leak, and death has also been shown to affect outcome.^48,49 As a result, many if not most of such patients present the day of surgery already harboring highly pathogenic strains of bacteria expressing a potentially virulent and resistant phenotype. The question remains, to what extent can dietary pre-habilitation contain the influence of all of these stressors on the microbiome?

What are the Mechanisms by Which Dietary Pre-Habilitation Can Alter Infection-Related Post-Operative Complications Such as Anastomotic Leak and SSIs?

When confronted with a high-risk patient (overweight/obesity, type 2 diabetes mellitus, hyperlipidemia, previous healthcare encounter, prior exposure to antibiotics⁵⁰) undergoing a high-risk procedure (intestinal stoma closure, major cancer resection, re-operative hip arthroplasty, etc.), post-operative infection-related complications include SSIs and anastomotic leaks. As mentioned above, under today's mandated asepsis protocols, there is evidence that most SSIs develop as a result of gut-derived bacteria post-operatively migrating to the operative site via a Trojan horse-type mechanism.⁵ In addition, compelling evidence now exists that implicates gut pathogens in the etiology of anastomotic leak.⁵¹ Finally, a recent analysis demonstrated that as many as 50% of the pathogens isolated in an SSI are resistant to the antibiotic agents chosen for prophylaxis.²¹ Therefore, alternative measures beyond greater application of antibiotic agents are needed.

Dietary pre-habilitation prior to a planned operation has three major goals, the successful end points of which can now be confirmed by measurements made using next-generation technology: to reduce/eliminate/contain the number of AMR pathogens in the gut microbiome; to reduce/eliminate/contain the proliferation of collagenase producing bacteria in the gut; and to shift a Western-type diet microbiome toward that of a more low-fat, high-fiber type diet-related microbiome that is rich in key metabolites known to drive a recovery directed immune response (i.e., short chain fatty acids, tryptophan, and indoles). All of the hard end points are now measurable in stool via genetic sequencing (i.e., 16s rRNA, metagenomics) and metabolomics. Whereas data display can become highly complicated and often requires a biostatistician to generate, many software platforms are now available to upload data. Yet most importantly, any regimen that is chosen after a thorough dietary assessment by a registered dietician can now be tracked before, during, and after surgery and its efficacy correlated to outcome.

The mechanisms of dietary pre-habilitation are simple. Given the emerging role of the gut microbiome in health and disease, its role in post-operative infection-related complications and the rapid shift in the microbiome that occurs after a short course of dietary manipulation (i.e., two to three days), optimization of the microbiome with a pre-operative dietary intervention (i.e., dietary pre-habilitation) is feasible and practical. The most studied mechanism of this effect is the ability of a high-fiber/low-fat diet to enrich the gut with key substrates (i.e., resistant starches) that are metabolized by key microbiota (i.e., anaerobes) to produce short-chain fatty acids (butyrate, proprionate, acetate) and other metabolites (tryptophan, indoles).^52–54 A high-fiber diet not only can act to suppress the proliferation of the low abundance proteobacteria (i.e., gram-negative bacteria), but it can also drive a recovery-directed immune response both within the mucosa and systemically.¹⁰

Given that the typical diet of a Western industrialized nation might be one in which there is high fat, high meat consumption, and low fiber, shifting its effect on the microbiome such that short-chain fatty acids and other key metabolites are enriched in the gut microbiome seems logical and practical. Even in the face of antibiotic agents, which are commonly prescribed in high-risk surgery, dietary pre-habilitation may offer some protection against the proliferation of renegade pathogens such as Clostridioides difficile⁵⁵ via short-chain fatty acid enrichment of the gut microbiome.

Conclusions

Dietary pre-habilitation prior to high-risk surgery is an approach that is gaining popularity as a practical method to prevent infection-related complications after major surgery. The efficacy of this approach can now be readily tested by combining clinical metadata to measures of the gut microbiome via expelled feces or via a rectal swab. However, prospective randomized trials in humans will be required to formally the hypothesis that dietary pre-habilitation can reduce anastomotic leaks and SSIs after high-risk surgery.

Funding Information

Supported in part by National Institutes of Health RO1 2R01GM62344-21.

Author Disclosure Statement

Dr. Alverdy is the founder and chief research officer of Covira Surgical, a University of Chicago company focused on post-operative infection prevention.