Effect of Surgery on Postoperative Levels of the Gut Homeostasis-Regulating Enzyme Intestinal Alkaline Phosphatase.

BACKGROUND: Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery. STUDY DESIGN: Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS. RESULTS: Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009). CONCLUSIONS: Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD.

Incorporating Well-Being into Mentorship Meetings: A Case Demonstration at Massachusetts General Hospital Department of Surgery a Harvard Medical School Affiliate.

Surgeons have been under great pressure during the COVID pandemic. Their careers are filled with fast paced decisions, life and death situations, and long hours at work. The COVID pandemic created more tasks and even new responsibilities at times, but when the operating rooms were closed down, there was less work. The COVID experience invited the opportunity to rethink mentoring in the surgery department at the Massachusetts General Hospital. The leadership experimented with a new style of mentoring which involved a team approach. In addition, they tried something else that was new: adding a lifestyle medicine expert and wellness coach to the mentoring team. The program was tested on 13 early stage surgeons who found the experience to be beneficial, and they commented that they wished they had it even earlier in their careers. Including a non-surgeon who was a lifestyle medicine physician and wellness coach added an element of whole person health that was acceptable to the surgeons and even embraced as the majority of them elected to follow up with one on one coaching after the mentoring meeting. This team mentoring program with senior surgeons and a lifestyle medicine expert is one that can be explored by other departments and other hospitals given its success at the department of surgery at Massachusetts General Hospital.

Stiffness Restricts the Stemness of the Intestinal Stem Cells and Skews Their Differentiation Toward Goblet Cells.

BACKGROUND & AIMS: Fibrosis and tissue stiffening are hallmarks of inflammatory bowel disease (IBD). We have hypothesized that the increased stiffness directly contributes to the dysregulation of the epithelial cell homeostasis in IBD. Here, we aim to determine the impact of tissue stiffening on the fate and function of the intestinal stem cells (ISCs). METHODS: We developed a long-term culture system consisting of 2.5-dimensional intestinal organoids grown on a hydrogel matrix with tunable stiffness. Single-cell RNA sequencing provided stiffness-regulated transcriptional signatures of the ISCs and their differentiated progeny. YAP-knockout and YAP-overexpression mice were used to manipulate YAP expression. In addition, we analyzed colon samples from murine colitis models and human IBD samples to assess the impact of stiffness on ISCs in vivo. RESULTS: We demonstrated that increasing the stiffness potently reduced the population of LGR5+ ISCs and KI-67+-proliferating cells. Conversely, cells expressing the stem cell marker, olfactomedin-4, became dominant in the crypt-like compartments and pervaded the villus-like regions. Concomitantly, stiffening prompted the ISCs to preferentially differentiate toward goblet cells. Mechanistically, stiffening increased the expression of cytosolic YAP, driving the extension of olfactomedin-4+ cells into the villus-like regions, while it induced the nuclear translocation of YAP, leading to preferential differentiation of ISCs toward goblet cells. Furthermore, analysis of colon samples from murine colitis models and patients with IBD demonstrated cellular and molecular remodeling reminiscent of those observed in vitro. CONCLUSIONS: Collectively, our findings highlight that matrix stiffness potently regulates the stemness of ISCs and their differentiation trajectory, supporting the hypothesis that fibrosis-induced gut stiffening plays a direct role in epithelial remodeling in IBD.

Institutional Surgical Response and Associated Volume Trends Throughout the COVID-19 Pandemic and Postvaccination Recovery Period.

Importance: The COVID-19 pandemic is associated with decreased surgical procedure volumes, but existing studies have not investigated this association beyond the end of 2020, analyzed changes during the post-vaccine release period, or quantified these changes by patient acuity. Objective: To quantify changes in the volume of surgical procedures at a 1017-bed academic quaternary care center from January 6, 2019, to December 31, 2021. Design, Setting, and Participants: In this cohort study, 129 596 surgical procedure volumes were retrospectively analyzed during 4 periods: pre-COVID-19 (January 6, 2019, to January 4, 2020), COVID-19 peak (March 15, 2020, to May 2, 2020), post-COVID-19 peak (May 3, 2020, to January 2, 2021), and post-vaccine release (January 3, 2021, to December 31, 2021). Surgery volumes were analyzed by subspecialty and case class (elective, emergent, nonurgent, urgent). Statistical analysis was by autoregressive integrated moving average modeling. Main Outcomes and Measures: The primary outcome of this study was the change in weekly surgical procedure volume across the 4 COVID-19 periods. Results: A total of 129 596 records of surgical procedures were reviewed. During the COVID-19 peak, overall weekly surgical procedure volumes (mean [SD] procedures per week, 406.00 [171.45]; 95% CI, 234.56-577.46) declined 44.6% from pre-COVID-19 levels (mean [SD] procedures per week, 732.37 [12.70]; 95% CI, 719.67-745.08; P < .001). This weekly volume decrease occurred across all surgical subspecialties. During the post-COVID peak period, overall weekly surgical volumes (mean [SD] procedures per week, 624.31 [142.45]; 95% CI, 481.85-766.76) recovered to only 85.8% of pre-COVID peak volumes (P < .001). This insufficient recovery was inconsistent across subspecialties and case classes. During the post-vaccine release period, although some subspecialties experienced recovery to pre-COVID-19 volumes, others continued to experience declines. Conclusions and Relevance: This quaternary care institution effectively responded to the pressures of the COVID-19 pandemic by substantially decreasing surgical procedure volumes during the peak of the pandemic. However, overall surgical procedure volumes did not fully recover to pre-COVID-19 levels well into 2021, with inconsistent recovery rates across subspecialties and case classes. These declines suggest that delays in surgical procedures may result in potentially higher morbidity rates in the future. The differential recovery rates across subspecialties may inform institutional focus for future operational recovery.

Survival After Adrenalectomy for Metastatic Lung Cancer.

BACKGROUND: Adrenal metastasectomy is associated with increased survival in non-small cell lung cancer (NSCLC) with isolated adrenal metastases. Although clinical use of adrenal metastasectomy has expanded, indications remain poorly defined. The aim of this study was to evaluate the clinical benefit of adrenal metastasectomy for all lung cancer subtypes. PATIENTS AND METHODS: We performed a retrospective cohort study of patients who underwent adrenal metastasectomy for metastatic lung cancer at six institutions between 2001 and 2015. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Cox proportional hazards regressions and Kaplan-Meier survival analysis were performed. RESULTS: For 122 patients, the mean age was 60.5 years and 49.2% were female. Median time to detection of the metastasis was 11 months, and 41.8% were ipsilateral to the primary lung cancer. Median DFS was 40 months (1 year: 64.8%; 5 year: 42.9%). Factors associated with longer DFS included primary tumor resection [hazard ratio (HR): 0.001; p = 0.005], longer time to adrenal metastasis (HR: 0.94; p = 0.005), and ipsilateral metastases (HR: 0.13; p = 0.004). Shorter DFS corresponded with older age (HR: 1.11; p = 0.01), R1 resection (HR: 8.94; p = 0.01), adjuvant radiation (HR: 9.45; p = 0.02), and open adrenal metastasectomy (HR: 10.0; p = 0.03). Median OS was 47 months (1 year: 80.2%; 5 year: 35.2%). Longer OS was associated with ipsilateral metastasis (HR: 0.55; p = 0.02) and adjuvant chemotherapy (HR: 0.35; p = 0.02). Shorter OS was associated with extra-adrenal metastases at adrenalectomy (HR: 3.52; p = 0.007), small cell histology (HR: 15.0; p = 0.04), and lung radiation (HR: 3.37; p = 0.002). DISCUSSION: Durable survival was observed in patients undergoing adrenal metastasectomy and should be considered for isolated adrenal metastases of NSCLC. Small cell histology and extra-adrenal metastases are relative contraindications to adrenal metastasectomy.

Delay to Intervention for Complicated Diverticulitis is Associated with Higher Inpatient Mortality.

BACKGROUND: Patients with diverticular disease complicated by abscess and/or perforation represent the most severely afflicted with the highest mortality and poorest outcomes. This study investigated patient and operative factors associated with poor outcomes from diverticulitis complicated by abscess or perforation. METHODS: We analyzed the National Inpatient Sample to identify inpatient discharges for colonic diverticulitis in the United States from 1/1988 to 9/2015. We identified patients with perforation and/or intestinal abscess based on ICD-9 codes. The primary outcome was inpatient mortality. RESULTS: During the study period, a total of 993,220 patients were discharged with diverticulitis from sampled U.S. hospitals. From this group, 10.7% had an abscess and 1.0% had a perforation associated with diverticular disease. Inpatient mortality of diverticulitis patients with a perforation was 5.4% compared to 1.5% in those without a perforation (p<0.001). Patients with a perforation who underwent surgery had an inpatient mortality of 6.3% vs. 3.0% mortality amongst patients with a perforation who did not undergo an operation (p<0.001). Patients with a perforation that underwent surgery had a 31% increased mortality risk for each day after admission that a procedure was delayed (OR 1.31, CI 1.05-1.78; p=0.03). Mortality risk was increased for patients with either abscess or perforation who underwent surgery if they were female, age ≥65, higher comorbidity, were admitted urgently, underwent peritoneal lavage, or had a post-procedural complication. CONCLUSIONS: Patients with perforated diverticular disease had substantial associated inpatient mortality compared to those with uncomplicated diverticulitis. This increased risk may be associated with performance of peritoneal lavage or because of a delay to procedural intervention.

A role for intestinal alkaline phosphatase in preventing liver fibrosis.

Rationale: Liver fibrosis is frequently associated with gut barrier dysfunction, and the lipopolysaccharides (LPS) -TLR4 pathway is common to the development of both. Intestinal alkaline phosphatase (IAP) has the ability to detoxify LPS, as well as maintain intestinal tight junction proteins and gut barrier integrity. Therefore, we hypothesized that IAP may function as a novel therapy to prevent liver fibrosis. Methods: Stool IAP activity from cirrhotic patients were determined. Common bile duct ligation (CBDL) and Carbon Tetrachloride-4 (CCl4)-induced liver fibrosis models were used in WT, IAP knockout (KO), and TLR4 KO mice supplemented with or without exogenous IAP in their drinking water. The gut barrier function and liver fibrosis markers were tested. Results: Human stool IAP activity was decreased in the setting of liver cirrhosis. In mice, IAP activity and genes expression decreased after CBDL and CCl4 exposure. Intestinal tight junction related genes and gut barrier function were impaired in both models of liver fibrosis. Oral IAP supplementation attenuated the decrease in small intestine tight junction protein gene expression and gut barrier function. Liver fibrosis markers were significantly higher in IAP KO compared to WT mice in both models, while oral IAP rescued liver fibrosis in both WT and IAP KO mice. In contrast, IAP supplementation did not attenuate fibrosis in TLR4 KO mice in either model. Conclusions: Endogenous IAP is decreased during liver fibrosis, perhaps contributing to the gut barrier dysfunction and worsening fibrosis. Oral IAP protects the gut barrier and further prevents the development of liver fibrosis via a TLR4-mediated mechanism.

Adrenalectomy for Secondary Malignancy: Patients, Outcomes, and Indications.

OBJECTIVE: The goal of this study was to examine a multi-institutional experience with adrenal metastases to describe survival outcomes and identify subpopulations who benefit from adrenal metastasectomy. BACKGROUND: Adrenalectomy for metastatic disease is well-described, although indications and outcomes are incompletely defined. METHODS: A retrospective cohort study was performed of patients undergoing adrenalectomy for secondary malignancy (2002-2015) at 6 institutions. The primary outcomes were disease free survival (DFS) and overall survival (OS). Analysis methods included Kaplan-Meier and Cox proportional hazards. RESULTS: Of 269 patients, mean age was 60.1 years; 50% were male. The most common primary malignancies were lung (n = 125, 47%), renal cell (n = 38, 14%), melanoma (n = 33, 12%), sarcoma (n = 18, 7%), and colorectal (n = 12, 5%). The median time to detection of adrenal metastasis after initial diagnosis of the primary tumor was 17 months (interquartile range: 6-41). Post-adrenalectomy, the median DFS was 18 months (1-year DFS: 54%, 5-year DFS: 31%). On multivariable analysis, lung primary was associated with longer DFS [hazard ratio (HR): 0.49, P = 0.008). Extra-adrenal oligometastatic disease at initial presentation (HR: 1.84, P = 0.016), larger tumor size (HR: 1.07, P = 0.013), chemotherapy as treatment of the primary tumor (HR: 2.07 P = 0.027) and adjuvant chemotherapy (HR: 1.95, P = 0.009) were associated with shorter DFS. Median OS was 53 months (1-year OS: 83%, 5-year OS: 43%). On multivariable analysis, extra-adrenal oligometastatic disease at adrenalectomy (HR: 1.74, P = 0.031), and incomplete resection of adrenal metastasis (R1 margins; HR: 1.62, P = 0.034; R2 margins; HR: 5.45, P = 0.002) were associated with shorter OS. CONCLUSIONS: Durable survival is observed in patients undergoing adrenal metastasectomy and should be considered for subjects with isolated adrenal metastases.

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.

Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis.

Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now examined the relevance of phosphate groups in the lipid A moiety in this process. The effects of mono-phosphoryl and di-phosphoryl lipid A (MPLA and DPLA, respectively) were studied in vitro and LPS-dephosphorylating activity was studied in normal and fibrotic mouse and human livers. The effects of intestinal AP were studied in mice with CCL4-induced liver fibrosis. DPLA strongly stimulated fibrogenic and inflammatory activities in primary rat hepatic stellate cells (rHSCs) and RAW264.7 macrophages with similar potency as full length LPS. However, MPLA did not affect any of the parameters. LPS-dephosphorylating activity was found in mouse and human livers and was strongly increased during fibrogenesis. Treatment of fibrotic mice with intravenous intestinal-AP significantly attenuated intrahepatic desmin+- and αSMA+ -HSC and CD68+- macrophage accumulation. In conclusion, the lack of biological activity of MPLA, contrasting with the profound activities of DPLA, shows the relevance of LPS-dephosphorylating activity. The upregulation of LPS-dephosphorylating activity in fibrotic livers and the protective effects of exogenous AP during fibrogenesis indicate an important physiological role of intestinal-derived AP during liver fibrosis.

Targeting the gut to prevent sepsis from a cutaneous burn.

Severe burn injury induces gut barrier dysfunction and subsequently a profound systemic inflammatory response. In the present study, we examined the role of the small intestinal brush border enzyme, intestinal alkaline phosphatase (IAP), in preserving gut barrier function and preventing systemic inflammation after burn wound infection in mice. Mice were subjected to a 30% total body surface area dorsal burn with or without intradermal injection of Pseudomonas aeruginosa. Mice were gavaged with 2000 units of IAP or vehicle at 3 and 12 hours after the insult. We found that both endogenously produced and exogenously supplemented IAP significantly reduced gut barrier damage, decreased bacterial translocation to the systemic organs, attenuated systemic inflammation, and improved survival in this burn wound infection model. IAP attenuated liver inflammation and reduced the proinflammatory characteristics of portal serum. Furthermore, we found that intestinal luminal contents of burn wound-infected mice negatively impacted the intestinal epithelial integrity compared with luminal contents of control mice and that IAP supplementation preserved monolayer integrity. These results indicate that oral IAP therapy may represent an approach to preserving gut barrier function, blocking proinflammatory triggers from entering the portal system, preventing gut-induced systemic inflammation, and improving survival after severe burn injuries.

Intestinal alkaline phosphatase targets the gut barrier to prevent aging.

Gut barrier dysfunction and gut-derived chronic inflammation play crucial roles in human aging. The gut brush border enzyme intestinal alkaline phosphatase (IAP) functions to inhibit inflammatory mediators and also appears to be an important positive regulator of gut barrier function and microbial homeostasis. We hypothesized that this enzyme could play a critical role in regulating the aging process. We tested the role of several IAP functions for prevention of age-dependent alterations in intestinal homeostasis by employing different loss-of-function and supplementation approaches. In mice, there is an age-related increase in gut permeability that is accompanied by increases in gut-derived portal venous and systemic inflammation. All these phenotypes were significantly more pronounced in IAP-deficient animals. Oral IAP supplementation significantly decreased age-related gut permeability and gut-derived systemic inflammation, resulted in less frailty, and extended lifespan. Furthermore, IAP supplementation was associated with preserving the homeostasis of gut microbiota during aging. These effects of IAP were also evident in a second model system, Drosophilae melanogaster. IAP appears to preserve intestinal homeostasis in aging by targeting crucial intestinal alterations, including gut barrier dysfunction, dysbiosis, and endotoxemia. Oral IAP supplementation may represent a novel therapy to counteract the chronic inflammatory state leading to frailty and age-related diseases in humans.

Bowel Function After J-Pouch May Be More Complex Than Previously Appreciated: A Comprehensive Analysis to Highlight Existing Knowledge Gaps.

BACKGROUND: Functional outcomes following J-pouch for ulcerative colitis have been studied, but lack standardization in which symptoms are reported. Furthermore, the selection of symptoms studied has not been patient centered. OBJECTIVE: This study aimed to utilize a validated bowel function survey to determine which symptoms are present after J-pouch creation, and whether patients display a functional profile similar to low anterior resection syndrome. DESIGN: This study is a retrospective analysis of a prospectively maintained single-center database. SETTINGS: This study was conducted at the colorectal surgery center of a tertiary care academic hospital PATIENTS:: Included were 159 patients with J-pouch, ≥6 months after ileostomy reversal. MAIN OUTCOME MEASURES: The primary outcomes were individual answers to the Memorial Sloan Kettering Cancer Center Bowel Function Instrument. The original Bowel Function Instrument validation cohort was used as an historical comparison (n = 127). RESULTS: The mean total Bowel Function Instrument score for the J-pouch cohort was 59.9 ± 9.7 compared with a reported average score of 63.7 ± 11.6 for patients with low anterior resection in the validation cohort (p < 0.001), indicating worse bowel function in patients with J-pouch. When evaluating the Bowel Function Instrument subscales, patients with J-pouch reported frequency subscale scores of 18.2 ± 3.8, diet scores of 12.2 ± 3.8, and urgency scores of 15.9 ± 3.7, compared with 21.7 ± 4.5 (p < 0.001), 14.1 ± 3.7 (p < 0.001), and 15.0 ± 3.9 (p = 0.04) for patients undergoing rectal resection. Furthermore, 90.4% of patients with J-pouch state that they are sometimes, rarely, or never able to wait 15 minutes to get to the toilet. In addition, 56.4% of patients report having another bowel movement within 15 minutes of the last bowel movement, sometimes, always, or most of the time, and 50.6% of patients say that they sometimes, rarely, or never feel like their bowels have been totally emptied after a bowel movement. LIMITATIONS: This study is limited because it took place at a single center and the Bowel Function Instrument was only validated for patients undergoing rectal resection. CONCLUSIONS: Patients that undergo J-pouch surgery exhibit a constellation of bowel function symptoms that is more complex than fecal incontinence and frequency alone, despite the focus on these functional outcomes in the literature. See Video Abstract at http://links.lww.com/DCR/B73. LA FUNCIÓN INTESTINAL DESPUÉS DE LA BOLSA EN J PUEDE SER MÁS COMPLEJA DE LO QUE SE APRECIABA ANTERIORMENTE: UN ANÁLISIS EXHAUSTIVO PARA RESALTAR LAS BRECHAS DE CONOCIMIENTO EXISTENTES: Se han estudiado los resultados funcionales después de la bolsa en J para la colitis ulcerosa, pero carecen de estandarización en la que se informen los síntomas. Además, la selección de los síntomas estudiados no se ha centrado en el paciente.Utilizar una encuesta validada de la función intestinal para determinar qué síntomas están presentes después de la bolsa en J y si los pacientes muestran un perfil funcional similar al síndrome de resección anterior baja.Análisis retrospectivo de una base de datos de un solo centro mantenida prospectivamente.Centro de cirugía colorrectal de un hospital académico de atención terciaria.159 pacientes con bolsa en J, ≥6 meses después de la reversión de ileostomía.Instrumento para la función intestinal del "Memorial Sloan Kettering Cancer Center"; cohorte de validación original de instrumentos de función intestinal utilizada como comparación histórica (n = 127).La puntuación media total del instrumento de función intestinal para la cohorte de bolsa J fue 59.9 ± 9.7 en comparación con un puntaje promedio reportado de 63.7 ± 11.6 para pacientes con resección anterior baja en la cohorte de validación (p < 0.001), lo que indica peor función intestinal en pacientes con bolsa en J. Al evaluar las subescalas del instrumento de función intestinal, los pacientes con bolsa en J informaron puntuaciones de subescala de frecuencia de 18.2 ± 3.8, puntuaciones de dieta de 12.2 ± 3.8 y puntuaciones de urgencia de 15.9 ± 3.7, en comparación con 21.7 ± 4.5 (p < 0.001), 14.1 ± 3.7 (p < 0.001) y 15.0 ± 3.9 (p = 0.04) respectivamente para pacientes con resección rectal. Además, el 90.4% de los pacientes con bolsa en J afirman que a veces, rara vez o nunca pueden esperar 15 minutos para llegar al baño. Además, el 56.4% de los pacientes reportan haber tenido otra evacuación intestinal dentro de los 15 minutos posteriores a la última evacuación intestinal, a veces, siempre o la mayor parte del tiempo, y el 50.6% de los pacientes dicen que a veces, rara vez o nunca sienten que sus intestinos han sido vaciados totalmente después de una evacuación intestinal.Estudio en un solo centro, instrumento de función intestinal validado solo para pacientes con resección rectalLos pacientes que se someten a una bolsa en J exhiben una constelación de síntomas de la función intestinal que es más compleja que la incontinencia fecal y la frecuencia sola, a pesar del enfoque en estos resultados funcionales en la literatura.Consulte Video Resumen en http://links.lww.com/DCR/B73. (Traducción-Dr. Gonzalo Federico Hagerman).

Challenges in IBD Research: Preclinical Human IBD Mechanisms.

Preclinical human IBD mechanisms is part of five focus areas of the Challenges in IBD research document, which also include environmental triggers, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the preclinical human IBD mechanisms manuscript is focused on highlighting the main research gaps in the pathophysiological understanding of human IBD. These research gap areas include: 1) triggers of immune responses; 2) intestinal epithelial homeostasis and wound repair; 3) age-specific pathophysiology; 4) disease complications; 5) heterogeneous response to treatments; and 6) determination of disease location. As an approach to address these research gaps, the prioritization of reverse translation studies is proposed in which clinical observations are the foundation for experimental IBD research in the lab, and for the identification of new therapeutic targets and biomarkers. The use of human samples in validating basic research findings and development of precision medicine solutions is also proposed. This prioritization aims to put emphasis on relevant biochemical pathways and humanized in vitro and in vivo models that extrapolate meaningfully to human IBD, to eventually yield first-in-class and effective therapies.

Targeting bacterial quorum sensing shows promise in improving intestinal barrier function following burn­site infection.

Burn­site infections, commonly due to Pseudomonas aeruginosa, have been associated with deranged intestinal integrity, allowing bacteria and their products to translocate from the gut to the circulatory system. The P. aeruginosa quorum sensing (QS) transcription factor MvfR (PqsR) controls the expression of numerous virulence factors, and the synthesis of several toxic products. However, the role of QS in intestinal integrity alterations, to the best of our knowledge, has not been previously investigated. Using a proven anti­MvfR, anti­virulence agent, the in vivo results of the present study revealed that inhibition of MvfR function significantly decreased Fluorescein Isothiocyanate­Dextran (FITC­Dextran) flow from the intestine to the systemic circulation, diminished bacterial translocation from the intestine to mesenteric lymph nodes (MLNs), and improved tight junction integrity in thermally injured and infected mice. In addition, the MvfR antagonist administration alleviates the intestinal inflammation, as demonstrated by reduced ileal TNF­α and fecal lipocalin­2 concentrations. In addition, it is associated with lower levels of circulating endotoxin and decreased P. aeruginosa dissemination from the burn wound to the ileum. Collectively, these results hold great promise that the inhibition of this QS system mitigates gut hyperpermeability by attenuating the derangement of morphological and immune aspects of the intestinal barrier, suggesting that MvfR function is crucial in the deterioration of intestinal integrity following P. aeruginosa burn­site infection. Therefore, an anti­virulence approach targeting MvfR, could potentially offer a novel therapeutic approach against multi­drug resistant P. aeruginosa infections following thermal injuries. Since this approach is targeting virulence pathways that are non­essential for growth or viability, our strategy is hypothesized to minimize the development of bacterial resistance, and preserve the beneficial enteric microbes, while improving intestinal integrity that is deranged as a result of burn and infection.