Western Diet-induced Transcriptional Changes in Anastomotic Tissue Is Associated With Early Local Recurrence in a Mouse Model of Colorectal Surgery.

OBJECTIVE: To determine the timeframe and associated changes in the microenvironment that promote the development of a diet-induced local-regional recurrence in a mouse model of colorectal surgery. BACKGROUND: Postoperative recurrence and metastasis occur in up to 30% of patients undergoing attempted resection for colorectal cancer (CRC). The underlying mechanisms that drive the development of postoperative recurrences are poorly understood. Preclinical studies have demonstrated a diet and microbial-driven pathogenesis of local-regional recurrence, yet the precise mechanisms remain undefined. METHODS: BALB/C mice were fed a western diet (WD) or standard diet (SD), underwent a colon resection and anastomosis, given an Enterococcus faecalis enema on postoperative day (POD) 1, and subjected to a CT26 cancer cell enema (mimicking shed cancer cells) on POD2. Mice were sacrificed between POD3 and POD7 and cancer cell migration was tracked. Dynamic changes in gene expression of anastomotic tissue that were associated with cancer cell migration was assessed. RESULTS: Tumor cells were identified in mice fed either a SD or WD in both anastomotic and lymphatic tissue as early as on POD3. Histology demonstrated that these tumor cells were viable and replicating. In WD-fed mice, the number of tumor cells increased over the early perioperative period and was significantly higher than in mice fed a SD. Microarray analysis of anastomotic tissue found that WD-fed mice had 11 dysregulated genes associated with tumorigenesis. CONCLUSIONS: A WD promotes cancer cells to permeate a healing anastomosis and migrate into anastomotic and lymphatic tissue forming viable tumor nodules. These data offer a novel recurrence pathogenesis by which the intestinal microenvironment promotes a CRC local-regional recurrence.

Rising Mortality in Pediatric Self-Inflicted Firearm Trauma Associated With Distinct Anatomic Injury.

INTRODUCTION: Self-inflicted injuries are the second leading cause of pediatric (10-18 y old) mortality. Self-inflicted firearm trauma (SIFT) was responsible for up to half of these deaths in certain age groups. We hypothesized that SIFT prevalence has increased and is associated with specific demographics, injury patterns, and outcomes. MATERIALS AND METHODS: Data were abstracted from the 2007-2018 American College of Surgeons (ACS) Trauma Quality Programs Participant Use Files (TQP-PUF). Pediatric (1-17 yold) victims of firearm violence were eligible. Age, race, gender, anatomic region, and intent were abstracted. Variables were analyzed using chi-squared tests, t-tests, and single-variate linear regression models. Temporal trends were analyzed using ANCOVA tests. Multivariate logistic regressions were conducted to identify factors influencing mortality. Significance was P < 0.05. RESULTS: There were 41,239 pediatric firearm trauma patients (SIFT: 5.5% [n = 2272]). SIFT incidence increased over the 12-y period (2007 (n = 67) versus 2018 (n = 232), P < 0.05). SIFT was significantly associated with Caucasian race, 67% (n = 1537), teenagers, 90% (n = 2056), male gender, 87% (n = 1978), and a higher median injury severity score (ISS) than other intents of injury (SIFT: 20.0 (IQR: 9.0, 25.0) versus other: 9.0 (IQR: 1.0-13.0), P < 0.001). The SIFT mortality rate was 44% (n = 1005). On multivariate regression head gunshot wounds (OR: 21.1, 95% C.I.: 9.9-45.2, P = 0.001), and ISS (OR:1.1, 95% C.I.: 1.1-1.1, P = 0.001) were significantly associated with mortality. Compared to other intents, SIFT mortality rates increased at a higher annual rate (P < 0.001). CONCLUSIONS: Comprehensive local and federal policy changes to reduce firearms access and increase pediatric mental health support may mitigate these injuries.

Is Previous Postoperative Infection an Independent Risk Factor for Postoperative Infection after Second Unrelated Abdominal Operation?

BACKGROUND: Infections after abdominal surgery remain a significant problem. Although preoperative antibiotic prophylaxis is a primary strategy used to reduce postoperative infections, it is typically prescribed based on standardized protocols, without attention to previous infection or antibiotic history. Patients with a previous infection after surgery may be at higher risk for infectious complications after subsequent operations owing to antibiotic resistance. We hypothesized that a previous postoperative infection is a significant risk factor for the development of infection after a second unrelated surgery. STUDY DESIGN: We performed a retrospective study of patients who had undergone 2 unrelated abdominal operations at a tertiary care center from 2012 to 2018. Clinical variables and microbiological culture results were abstracted. Univariate and multivariable regression models were constructed. RESULTS: Of 758 patients, 15.0% (n = 114) developed an infection after the first operation. After the second operation, 22.8% (n = 26) of those with a previous infection developed another infection, whereas the incidence of an infection after the second operation was only 9.5% (n = 61) in patients who did not develop an infection after the first operation. Multivariable analysis demonstrated that previous infection (odds ratio 2.49, 95% CI 1.46 to 4.25) was associated with future infection risk. Microbiological analysis found that infections after the second surgery were significantly more likely to be antibiotic resistant than infections after the first surgery (82.3% vs 64.1%; p = 0.036). Strikingly, 49% of infections after the second surgery were resistant to the antibiotic prophylaxis given at the time of incision. CONCLUSIONS: Previous postoperative infection is an independent risk factor for a subsequent postoperative infection and is associated with resistance to standard prophylaxis. Individualization of antibiotic prophylaxis in patients with a previous postoperative infection is warranted.

Derivation and validation of an improved pediatric shock index for predicting need for early intervention and outcomes in pediatric trauma.

BACKGROUND: Shock index, pediatric age adjusted (SIPA), has been widely applied in pediatric trauma but has limited precision because of the reference ranges used in its derivation. We hypothesized that a pediatric shock index (PSI) equation based on age-based vital signs would outperform SIPA. METHODS: A retrospective cohort of trauma patients aged 1 to 18 years from Trauma Quality Programs - Participant Use File 2010 to 2018 was performed. A random 70% training subset was used to derive Youden index-optimizing shock index (SI) cutoffs by age for blood transfusion within 4 hours. We used linear regression to derive equations representing the PSI cutoff for children 12 years or younger and 13 years or older. For children 13 years or older, the well-established SI of 0.9 remained optimal, consistent with SIPA and other indices. For children 12 years or younger in the 30% validation subset, we compared our age-based PSI to SIPA as predictors of early transfusion, mortality, pediatric intensive care unit admission, and injury severity score of ≥25. For bedside use, a simplified "rapid" pediatric shock index (rPSI) equation was also derived and compared with SIPA. RESULTS: A total of 439,699 patients aged 1 to 12 years met the inclusion criteria with 2,718 (1.3% of those with available outcome data) requiring transfusion within 4 hours of presentation. In the validation set, positive predictive values for early transfusion were higher for PSI (8.3%; 95% confidence interval [CI], 7.5-9.1%) and rPSI (6.3%; 95% CI, 5.7-6.9%) than SIPA (4.3%; 95% CI, 3.9-4.7%). For early transfusion, negative predictive values for both PSI (99.3%; 95% CI, 99.2-99.3%) and rPSI (99.3%; 95% CI, 99.2-99.4%) were similar to SIPA (99.4%; 95% CI, 99.3-99.4%). CONCLUSION: We derived the PSI and rPSI for use in pediatric trauma using empiric, age-based SI cutoffs. The PSI and rPSI achieved higher positive predictive values and similar negative predictive values to SIPA in predicting the need for early blood transfusion and mortality. LEVEL OF EVIDENCE: Prognostic/Epidemiological; level III.

A Novel Nonantibiotic Gut-directed Strategy to Prevent Surgical Site Infections.

OBJECTIVE: To determine the efficacy of an orally delivered phosphate-rich polymer, Pi-PEG, to prevent surgical site infection (SSI) in a mouse model of spontaneous wound infection involving gut-derived pathogens. BACKGROUND: Evidence suggests that pathogens originating from the gut microbiota can cause postoperative infection via a process by which they silently travel inside an immune cell and contaminate a remote operative site (Trojan Horse Hypothesis). Here, we hypothesize that Pi-PEG can prevent SSIs in a novel model of postoperative SSIs in mice. METHODS: Mice were fed either a standard chow diet (high fiber/low fat, SD) or a western-type diet (low fiber/high fat, WD), and exposed to antibiotics (oral clindamycin/intraperitoneal cefoxitin). Groups of mice had Pi-PEG added to their drinking water and SSI incidence was determined. Gross clinical infections wound cultures and amplicon sequence variant analysis of the intestinal contents and wound were assessed to determine the incidence and source of the developing SSI. RESULTS: In this model, consumption of a WD and exposure to antibiotics promoted the growth of SSI pathogens in the gut and their subsequent presence in the wound. Mice subjected to this model drinking water spiked with Pi-PEG were protected against SSIs via mechanisms involving modulation of the gut-wound microbiome. CONCLUSIONS: A nonantibiotic phosphate-rich polymer, Pi-PEG, added to the drinking water of mice prevents SSIs and may represent a more sustainable approach in lieu of the current trend of greater sterility and the use of more powerful and broader antibiotic coverage.

Alternative shock index cutoffs for pediatric patients outperform the Shock Index Pediatric Age-adjusted (SIPA) on strength of association with adverse outcomes in pediatric trauma patients.

BACKGROUND: The shock index is a tool for evaluating critically ill patients that is defined as the ratio of their heart rate divided by systolic blood pressure. The SI is associated with outcomes in adult trauma patients. The Shock Index Pediatric Age-adjusted was developed as a pediatric-specific tool to account for the physiologic differences of children of varying ages. There is growing interest in Shock Index Pediatric Age-adjusted, which is associated with adverse outcomes in pediatric trauma. We hypothesized that alternative shock index cutoffs based on the Advanced Trauma Life Support or the Pediatric Advanced Life Support vital sign reference ranges would outperform Shock Index Pediatric Age-adjusted. METHODS: We analyzed a retrospective cohort of pediatric trauma patients (age 1 to 16 years old) in the American College of Surgeons Trauma Quality Programs Participant Use File from 2010 to 2018. The primary outcome measure was in-hospital mortality. The Shock Index Pediatric Age-adjusted was compared to an Advanced Trauma Life Support-based and a Pediatric Advanced Life Support-based shock index cutoff system. Our findings were subsequently confirmed with a separate, internal validation data set. RESULTS: A total of 598,830 Trauma Quality Programs Participant Use File patients were included, 0.9% (n = 5,471) of whom died. For mortality, the Advanced Trauma Life Support-based system yielded the highest positive predictive value (15.8%; 95% confidence interval 15.0%-16.7%) compared with the Pediatric Advanced Life Support-based system (4.3%; 95% confidence interval 4.1%-4.5%). Both the Advanced Trauma Life Support-based and Pediatric Advanced Life Support-based systems achieved higher positive predictive values compared to Shock Index Pediatric Age-adjusted (2.6%; 95% confidence interval 2.5%-2.7%). The negative predictive values were not clinically different. Our findings were validated using a separate internal trauma database, in which the positive predictive value for mortality of the Advanced Trauma Life Support-based system was significantly higher than Shock Index Pediatric Age-adjusted (18.2% [95% confidence interval: 8.2%-32.7%] vs 2.9% [95% confidence interval: 1.6%-5.0%], P < .05). CONCLUSION: Advanced Trauma Life Support and Pediatric Advanced Life Support-based shock index cutoffs achieved higher positive predictive values and similar negative predictive values compared to Shock Index Pediatric Age-adjusted for adverse outcomes in pediatric trauma.

Defining Microbiome Readiness for Surgery: Dietary Prehabilitation and Stool Biomarkers as Predictive Tools to Improve Outcome.

OBJECTIVES: Determine whether preoperative dietary prehabilitation with a low-fat, high-fiber diet reverses the impact of Western diet (WD) on the intestinal microbiota and improves postoperative survival. BACKGROUND: We have previously demonstrated that WD fed mice subjected to an otherwise recoverable surgical injury (30% hepatectomy), antibiotics, and a short period of starvation demonstrate reduced survival (29%) compared to mice fed a low-fat, high-fiber standard chow (SD) (100%). METHODS: Mice were subjected to 6 weeks of a WD and underwent dietary pre-habilitation (3 days vs 7 days) with a SD prior to exposure to antibiotics, starvation, and surgery. 16S rRNA gene sequencing was utilized to determine microbiota composition. Mass spectrometry measured short chain fatty acids and functional prediction from 16S gene amplicons were utilized to determine microbiota function. RESULTS: As early as 24 hours, dietary prehabilitation of WD mice resulted in restoration of bacterial composition of the stool microbiota, transitioning from Firmicutes dominant to Bacteroidetes dominant. However, during this early pre-habilitation (ie, 3 days), stool butyrate per microbial biomass remained low and postoperative mortality remained unchanged from WD. Microbiota function demonstrated reduced butyrate contributing taxa as potentially responsible for failed recovery. In contrast, after 7 days of prehabilitation (7DP), there was greater restoration of butyrate producing taxa and survival after surgery improved (29% vs 79% vs 100%: WD vs 7DP vs SD, P < 0.001). CONCLUSIONS: The deleterious effects of WD on the gut microbiota can be restored after 7 days of dietary prehabilitation. Moreover, stool markers may define the readiness of the microbiome to withstand the process of surgery including exposure to antibiotics and short periods of starvation.

Novel Trauma Composite Score is superior to Injury Severity Score in predicting mortality across all ages.

BACKGROUND: Injury Severity Score (ISS) is a widely used metric for trauma research and center verification; however, it does not account for age-related physiologic parameters. We hypothesized that a novel age-based injury severity metric would better predict mortality. METHODS: Adult patients (≥18 years) sustaining blunt trauma (BT) or penetrating trauma (PT) were abstracted from the 2010 to 2016 National Trauma Data Bank. Admission vitals, Glasgow Coma Scale, ISS, mechanism, and outcomes were analyzed. Patients with incomplete/non-physiologic vital signs were excluded. For each age: (1) a cut point analysis was used to determine the ISS with the highest specificity and sensitivity for predicting mortality and (2) a linear discriminant analysis was performed using ISS, ISS greater than 16, Trauma and Injury Severity Score, and Revised Trauma Scale to compare each scoring system's mortality prediction. A novel injury severity metric, the trauma component score (TCS), was developed for each age using significant (p < 0.05) variables selected from Abbreviated Injury Scale scores, Glasgow Coma Scale, vital signs, and gender. Receiver operator curves were developed and the areas under the curve were compared between the TCS and other systems. RESULTS: There 777,794 patients studied (BT, 91.1%; PT, 8.9%). Blunt trauma patients were older (53.6 ± 21.3 years vs. 34.4 ± 13.8 years), had higher ISS scores (11.1 ± 8.5 vs. 8.5 ± 8.9), and lower mortality (2.9% vs. 3.4%) than PT patients (p < 0.05). When assessing the entire PT and BT cohort the optimal ISS cut point was 16. The optimal ISS was between 20 and 25 for BT younger than 70 years. For those older than 70 years, the optimal BT ISS steadily declined as age increased PT's cut point was 16 or less for all ages assessed. When the injury metrics were compared by area under the curve, our novel TCS more accurately predicted mortality across all ages in both BT and PT (p < 0.001). CONCLUSION: Injury Severity Score is a poor mortality predictor in older patients and those sustaining penetrating trauma. The age-based TCS is a superior metric for mortality prediction across all ages. LEVEL OF EVIDENCE: Clinical outcomes, Level IV.

Enterococcus faecalis Is Associated with Anastomotic Leak in Patients Undergoing Colorectal Surgery.

Background: Anastomotic leak is among the most dreaded complications in patients undergoing colorectal surgery. We have discovered that in rodents, collagenase-producing bacteria, particularly Enterococcus faecalis, promotes anastomotic leak by degrading healing anastomotic tissue. Yet, it is unclear if these organisms play a role in humans. Patients and Methods: Patients undergoing colorectal resection at the University of Chicago from July 2014 through June 2019 who developed a post-operative infection were stratified into infections that resulted from an anastomotic leak, a Hartmann pouch stump leak, or a deep infection without an associated staple line leak. Results: Forty-two patients had available culture data. Of these patients, 19 were found to have an anastomotic leak, 7 had a stump leak, and 16 had a deep infection that was not associated with a staple line. Enterococcus faecalis was identified in 24% of all infections and was associated with the development of anastomotic leak (p = 0.029). When the organisms were classified into their known ability to produce collagenase, 74% of patients with an anastomotic leak were colonized with collagenase-producing organisms, compared with only 28% of patients with a deep infection or stump leak (p = 0.022). Antibiotic-resistant organisms were more common in patients with anastomotic leak (p = 0.01). Conclusions: Collagenase-producing and antibiotic-resistant organisms are more prevalent in anastomotic leak infections compared with other deep or organ/space infections. This lends evidence to a bacterial driven pathogenesis of leak and suggests that targeting these organisms may be a novel strategy to reduce this complication.

Novel Trauma Composite Score is a more reliable predictor of mortality than Injury Severity Score in pediatric trauma.

BACKGROUND: The equivalent Injury Severity Score (ISS) cutoffs for severe trauma vary between adult (ISS, >16) and pediatric (ISS, >25) trauma. We hypothesized that a novel injury severity prediction model incorporating age and mechanism of injury would outperform standard ISS cutoffs. METHODS: The 2010 to 2016 National Trauma Data Bank was queried for pediatric trauma patients. Cut point analysis was used to determine the optimal ISS for predicting mortality for age and mechanism of injury. Linear discriminant analysis was implemented to determine prediction accuracy, based on area under the curve (AUC), of ISS cutoff of 25 (ISS, 25), shock index pediatric adjusted (SIPA), an age-adjusted ISS/abbreviated Trauma Composite Score (aTCS), and our novel Trauma Composite Score (TCS) in blunt trauma. The TCS consisted of significant variables (Abbreviated Injury Scale, Glasgow Coma Scale, sex, and SIPA) selected a priori for each age. RESULTS: There were 109,459 blunt trauma and 9,292 penetrating trauma patients studied. There was a significant difference in ISS (blunt trauma, 9.3 ± 8.0 vs. penetrating trauma, 8.0 ± 8.6; p < 0.01) and mortality (blunt trauma, 0.7% vs. penetrating trauma, 2.7%; p < 0.01). Analysis of the entire cohort revealed an optimal ISS cut point of 25 (AUC, 0.95; sensitivity, 0.86; specificity, 0.95); however, the optimal ISS ranged from 18 to 25 when evaluated by age and mechanism. Linear discriminant analysis model AUCs varied significantly for each injury metric when assessed for blunt trauma and penetrating trauma (penetrating trauma-adjusted ISS, 0.94 ± 0.02 vs. ISS 25, 0.88 ± 0.02 vs. SIPA, 0.62 ± 0.03; p < 0.001; blunt trauma-adjusted ISS, 0.96 ± 0.01 vs. ISS 25, 0.89 ± 0.02 vs. SIPA, 0.70 ± 0.02; p < 0.001). When injury metrics were assessed across age groups in blunt trauma, TCS and aTCS performed the best. CONCLUSION: Current use of ISS in pediatric trauma may not accurately reflect injury severity. The TCS and aTCS incorporate both age and mechanism and outperform standard metrics in mortality prediction in blunt trauma. LEVEL OF EVIDENCE: Retrospective review, level IV.

Sepsis and the Microbiome: A Vicious Cycle.

Sepsis has been characterized as a dysregulated host response to infection, and the role of the microbiome as a key influencer of this response is emerging. Disruption of the microbiome while treating sepsis with antibiotics can itself result in immune dysregulation. Alterations in the gut microbiome resulting from sepsis and its treatment have been implicated in organ dysfunction typical of sepsis across multiple tissues including the lung, kidney, and brain. Multiple microbiota-directed interventions are currently under investigation in the setting of sepsis, including fecal transplant, the administration of dietary fiber, and the use of antibiotic scavengers that attenuate the effects of antibiotics on the gut microbiota while allowing them to concentrate at the primary sites of infection. The emerging evidence shows that the gut microbiome interacts with various elements of the septic response, and provides yet another reason to consider the judicious use of antibiotics via antibiotic stewardship programs.

Recent release from prison - A novel risk factor for intimate partner homicide.

BACKGROUND: The United States has the highest per-capita incarceration rate and the largest prison population in the world. More than two thirds of recently incarcerated individuals will be arrested again within 3 years of release and may commit crimes as serious as homicide soon after discharge. The pattern of homicidal violence currently remains unknown for recently incarcerated homicide suspects (RIHS) and their victims. METHODS: A retrospective analysis of the 36 states included in the 2003 to 2017 National Violent Death Reporting System was performed with a focus on RIHS and their victims. Pearson χ2 and Wilcoxon rank sum tests were used for comparison. RESULTS: There were 249 RIHS in the database of the 14,561 homicides where suspect recent incarceration status was documented. Compared with not-recently incarcerated suspects, RIHS were more likely to be White (41% vs. 29%, p < 0.001) and male (97% vs. 91%, p < 0.001). Recently incarcerated homicide suspects more often had a known relationship with the victim (75% vs. 51%, p < 0.001), and these homicides more often occurred in the victim's own home (43% vs. 34%, p = 0.006). Intimate partner violence was a factor in 31% of the RIHS cases (vs. 17%, p < 0.001). The homicide weapon was most likely to be a firearm (57.8%, p < 0.001). Only 6.4% of homicides were due to mental health illness. Gang violence, while more common in the RIHS group, was still only a precipitating factor in 12.0% of the homicides (vs. 7.4%, p = 0.006). CONCLUSION: Recently incarcerated homicide suspects are more likely to kill a known person in their own home with a firearm, and these homicides are frequently categorized as intimate partner homicides. Gang violence and mental health are not frequent precipitating factors in these deaths. Additional future interventions are urgently needed to eliminate these preventable deaths by alerting previous or current intimate partners of those being discharged from the prison system.

The use of fecal microbiota transplant in sepsis.

Sepsis is defined as a dysregulated inflammatory response, which ultimately results from a perturbed interaction of both an altered immune system and the biomass and virulence of involved pathogens.  This response has been tied to the intestinal microbiota, as the microbiota and its associated metabolites play an essential role in regulating the host immune response to infection.  In turn, critical illness as well as necessary health care treatments result in a collapse of the intestinal microbiota diversity and a subsequent loss of health-promoting short chain fatty acids, such as butyrate, leading to the development of a maladaptive pathobiome.  These perturbations of the microbiota contribute to the dysregulated immune response and organ failure associated with sepsis.  Several case series have reported the ability of fecal microbiota transplant (FMT) to restore the host immune response and aid in recovery of septic patients.  Additionally, animal studies have revealed the mechanism of FMT rescue in sepsis is likely related to the ability of FMT to restore butyrate producing bacteria and alter the innate immune response aiding in pathogen clearance.  However, several studies have reported lethal complications associated with FMT, including bacteremia.  Therefore, FMT in the treatment of sepsis is and should remain investigational until a more detailed mechanism of how FMT restores the host immune response in sepsis is determined, allowing for the development of more fine-tuned microbiota therapies.

Spatial Compartmentalization of the Microbiome between the Lumen and Crypts Is Lost in the Murine Cecum following the Process of Surgery, Including Overnight Fasting and Exposure to Antibiotics.

The cecum is a unique region in the mammalian intestinal tract in which the microbiome is localized to two compartments, the lumen and the crypts. The microbiome within crypts is particularly important as it is in direct contact with lining epithelial cells including stem cells. Here, we analyzed the microbiome in cecum of mice using multiple techniques including metagenomics. The lumen microbiome comprised Firmicutes and Bacteroidetes whereas the crypts were dominated by Proteobacteria and Deferribacteres, and the mucus comprised a mixture of these 4 phyla. The lumen microbial functional potential comprised mainly carbon metabolism, while the crypt microbiome was enriched for genes encoding stress resistance. In order to determine how this structure, assembly, and function are altered under provocative conditions, we exposed mice to overnight starvation (S), antibiotics (A), and a major surgical injury (partial hepatectomy [H]), as occurs with major surgery in humans. We have previously demonstrated that the combined effect of this "SAH" treatment leads to a major disturbance of the cecal microbiota at the bottom of crypts in a manner that disrupts crypt cell homeostasis. Here, we applied the SAH conditions and observed a loss of compartmentalization in both composition and function of the cecal microbiome associated with major shifts in local physicochemical cues including decrease of hypoxia, increase of pH, and loss of butyrate production. Taken together, these studies demonstrated a defined order, structure, and function of the cecal microbiome that can be disrupted under provocative conditions such as major surgery and its attendant exposures.IMPORTANCE The proximal colon and cecum are two intestinal regions in which the microbiome localizes to two spatially distinct compartments, the lumen and crypts. The differences in composition and function of luminal and crypt microbiome in the cecum and the effect of physiological stress on their compartmentalization remain poorly characterized. Here, we characterized the composition and function of the lumen-, mucus-, and crypt-associated microbiome in the cecum of mice. We observed a highly ordered microbial architecture within the cecum whose assembly and function become markedly disrupted when provoked by physiological stress such as surgery and its attendant preoperative treatments (i.e., overnight fasting and antibiotics). Major shifts in local physicochemical cues including a decrease in hypoxia levels, an increase in pH, and a loss of butyrate production were associated with the loss of compositional and functional compartmentalization of the cecal microbiome.

Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?

A recent report by the National Institutes of Health on sepsis research has implied there is a trend to move away from mouse models of sepsis. The most commonly used animal model to study the pathogenesis of human sepsis is cecal ligation and puncture (CLP) in mice. The model has been the mainstay of sepsis research for decades and continues to be considered the gold standard to inform novel pathways of sepsis physiology and its therapeutic direction. As there have been many criticisms of the model, particularly regarding its relevance to human disease, how this model might be repurposed to be more reflective of the human condition begs discussion. In this piece, we compare and contrast the mouse microbiome of the CLP model to the emerging science of the microbiome of human sepsis and discuss the relevance for mice to harbor the specific pathogens present in the human microbiome during sepsis, as well as an underlying disease process to mimic the characteristics of those patients with undesirable outcomes. How to repurpose this model to incorporate these "human factors" is discussed in detail and suggestions offered.

Fecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity.

Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.

Mice Fed an Obesogenic Western Diet, Administered Antibiotics, and Subjected to a Sterile Surgical Procedure Develop Lethal Septicemia with Multidrug-Resistant Pathobionts.

Despite antibiotics and sterile technique, postoperative infections remain a real and present danger to patients. Recent estimates suggest that 50% of the pathogens associated with postoperative infections have become resistant to the standard antibiotics used for prophylaxis. Risk factors identified in such cases include obesity and antibiotic exposure. To study the combined effect of obesity and antibiotic exposure on postoperative infection, mice were allowed to gain weight on an obesogenic Western-type diet (WD), administered antibiotics and then subjected to an otherwise recoverable sterile surgical injury (30% hepatectomy). The feeding of a WD alone resulted in a major imbalance of the cecal microbiota characterized by a decrease in diversity, loss of Bacteroidetes, a bloom in Proteobacteria, and the emergence of antibiotic-resistant organisms among the cecal microbiota. When WD-fed mice were administered antibiotics and subjected to 30% liver resection, lethal sepsis, characterized by multiple-organ damage, developed. Notable was the emergence and systemic dissemination of multidrug-resistant (MDR) pathobionts, including carbapenem-resistant, extended-spectrum ß-lactamase-producing Serratia marcescens, which expressed a virulent and immunosuppressive phenotype. Analysis of the distribution of exact sequence variants belonging to the genus Serratia suggested that these strains originated from the cecal mucosa. No mortality or MDR pathogens were observed in identically treated mice fed a standard chow diet. Taken together, these results suggest that consumption of a Western diet and exposure to certain antibiotics may predispose to life-threating postoperative infection associated with MDR organisms present among the gut microbiota.IMPORTANCE Obesity remains a prevalent and independent risk factor for life-threatening infection following major surgery. Here, we demonstrate that when mice are fed an obesogenic Western diet (WD), they become susceptible to lethal sepsis with multiple organ damage after exposure to antibiotics and an otherwise-recoverable surgical injury. Analysis of the gut microbiota in this model demonstrates that WD alone leads to loss of Bacteroidetes, a bloom of Proteobacteria, and evidence of antibiotic resistance development even before antibiotics are administered. After antibiotics and surgery, lethal sepsis with organ damage developed in in mice fed a WD with the appearance of multidrug-resistant pathogens in the liver, spleen, and blood. The importance of these findings lies in exposing how the selective pressures of diet, antibiotic exposure, and surgical injury can converge on the microbiome, resulting in lethal sepsis and organ damage without the introduction of an exogenous pathogen.