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Objective: To evaluate population-based data on very preterm infants (<32 weeks gestation) operated for intestinal injuries, focusing on necrotising enterocolitis (NEC) and focal intestinal perforation (FIP)., Design: Nationwide, population-based registry cohort study., Setting: All 21 neonatal units in Norway., Participants: All very preterm infants born from 2014 through 2021 and admitted to a neonatal unit., Main Outcome Measures: Incidence of surgery for subgroups of intestinal injuries, medical record data on laboratory-radiology results, anatomical location of affected bowel, length of resections, number of re-operations, morbidities of prematurity and/or death before discharge., Results: Abdominal surgery was performed in 124/4009 (3.1%) very preterm infants and in 97/1300 (7.5%) extremely preterm infants <28 weeks. The main intestinal injuries operated were NEC (85/124; 69%), FIP (26/124; 21%) and 'other abdominal pathologies' (13/124; 10%). NEC cases were divided in (i) acute NEC, extensive disease (n=18), (ii) non-extensive disease (n=53) and (iii) NEC with surgery >3 days after disease onset (n=14). High lactate values immediately prior to surgery was predominantly seen in acute NEC-extensive disease and associated with high mortality. Other laboratory values could not discriminate between acute NEC and FIP. Timing of surgery for acute NEC and FIP overlapped. Radiological absence of portal venous gas was typical in FIP. Most infants (62.5%) underwent a stoma formation at initial surgery. The overall survival rate was 67% for NEC and 77% for FIP., Conclusion: NEC cases have different presentation and prognosis depending on the extent of bowel affected. Revised classifications for intestinal injuries in preterm infants may improve prognostication and better guide therapy., Competing Interests: Competing interests: CK has received honoraria from Chiesi as member of the board for the Nordic Neonatal Meeting., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

As primary flavonoids extracted from citrus fruits, hesperidin has been attracting attention widely for its capacity to act as antioxidants that are able to scavenge free radicals and reactive oxygen species (ROS). Many factors have made oxidative stress a risk factor for the occurrence of intestinal barrier injury, which is a serious health threat to human beings. However, little data are available regarding the underlying mechanism of hesperidin alleviating intestinal injury under oxidative stress. Recently, endoplasmic reticulum (ER) mitochondria contact sites (ERMCSs) have aroused increasing concerns among scholars, which participate in mitochondrial dynamics and Ca 2+ transport. In our experiment, 24 piglets were randomly divided into 4 groups. Piglets in the diquat group and hesperidin + diquat group received an intraperitoneal injection of diquat (10 mg/kg), while piglets in the hesperidin group and hesperidin + diquat group received hesperidin (300 mg/kg) with feed. The results indicated that hesperidin alleviated growth restriction and intestinal barrier injury in piglets compared with the diquat group. Hesperidin ameliorated oxidative stress and restored antioxidant capacity under diquat exposure. The mitochondrial dysfunction was markedly alleviated via hesperidin versus diquat group. Meanwhile, hesperidin alleviated ER stress and downregulated the PERK pathway. Furthermore, hesperidin prevented the disorder of ERMCSs by downregulating the level of ERMCS proteins, decreasing the percentage of mitochondria with ERMCSs/total mitochondria and the ratio of ERMCSs length/mitochondrial perimeter. These results suggested hesperidin could alleviate ERMCS disorder and prevent mitochondrial dysfunction, which subsequently decreased ROS production and alleviated intestinal barrier injury of piglets under oxidative stress.

Objectives: Intestinal ischemia-reperfusion (I/R) injury is a multifactorial and complex clinical pathophysiological process. Current research indicates that the pathogenesis of intestinal I/R injury involves various mechanisms, including ferroptosis. Methane saline (MS) has been demonstrated to primarily exert anti-inflammatory and antioxidant effects in I/R injury. In this study, we mainly investigated the effect of MS on ferroptosis in intestinal I/R injury and determined its potential mechanism., Methods: In vivo and in vitro intestinal I/R injury models were established to validate the relationship between ferroptosis and intestinal I/R injury. MS treatment was applied to assess its impact on intestinal epithelial cell damage, intestinal barrier disruption, and ferroptosis., Results: MS treatment led to a reduction in I/R-induced intestinal epithelial cell damage and intestinal barrier disruption. Moreover, similar to treatment with ferroptosis inhibitors, MS treatment reduced ferroptosis in I/R, as indicated by a decrease in the levels of intracellular pro-ferroptosis factors, an increase in the levels of anti-ferroptosis factors, and alleviation of mitochondrial damage. Additionally, the expression of Nrf2/HO-1 was significantly increased after MS treatment. However, the intestinal protective and ferroptosis inhibitory effects of MS were diminished after the use of M385 to inhibit Nrf2 in mice or si-Nrf2 in Caco-2 cells., Discussion: We proved that intestinal I/R injury was mitigated by MS and that the underlying mechanism involved modulating the Nrf2/HO-1 signaling pathway to decrease ferroptosis. MS could be a promising treatment for intestinal I/R injury.

Sepsis-associated liver injury (SALI) is a common complication of sepsis, which is characterized by systemic immune disorders induced by sepsis leading to liver damage. Currently, there are no effective treatments for SALI, which is related to its complex pathophysiological mechanisms. In recent years, the disorder of intestinal environment after sepsis has been considered as an important factor for SALI, but the specific molecular mechanism of the above process is still unclear. This article will review the pathological role and molecular mechanisms between intestinal environmental disturbance and SALI, aiming to analyze the potential research direction of SALI and identify potential therapeutic targets for its treatment.

Background: Severe acute pancreatitis (SAP) is an inflammatory disorder affecting the gastrointestinal system. Intestinal injury plays an important role in the treatment of severe acute pancreatitis. In this study, we mainly investigated the role of S1PR2 in regulating macrophage pyroptosis in the intestinal injury of severe acute pancreatitis., Methods: The SAP model was constructed using cerulein and lipopolysaccharide, and the expression of S1PR2 was inhibited by JTE-013 to detect the degree of pancreatitis and intestinal tissue damage in mice. Meanwhile, the level of pyroptosis-related protein was detected by western blot, the level of related mRNA was detected by PCR, and the level of serum inflammatory factors was detected by ELISA. In vitro experiments, LPS+ATP was used to construct the pyroptosis model of THP-1. After knockdown and overexpression of S1PR2, the pyroptosis proteins level was detected by western blot, the related mRNA level was detected by PCR, and the level of cell supernatant inflammatory factors were detected by ELISA. A rescue experiment was used to verify the sufficient necessity of the RhoA/ROCK pathway in S1PR2-induced pyroptosis. Meanwhile, THP-1 and FHC were co-cultured to verify that cytokines released by THP-1 after damage could regulate FHC damage., Results: Our results demonstrated that JTE-013 effectively attenuated intestinal injury and inflammation in mice with SAP. Furthermore, we observed a significant reduction in the expression of pyroptosis-related proteins within the intestinal tissue of SAP mice upon treatment with JTE-013. We confirmed the involvement of S1PR2 in THP-1 cell pyroptosis in vitro . Specifically, activation of S1PR2 triggered pyroptosis in THP-1 cells through the RhoA/ROCK signaling pathway. Moreover, it was observed that inflammatory factors released during THP-1 cell pyroptosis exerted an impact on cohesin expression in FHC cells., Conclusion: The involvement of S1PR2 in SAP-induced intestinal mucosal injury may be attributed to its regulation of macrophage pyroptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Peng, Zhu and Pan.)

Abstract: Background : This study aims to determine the impact and mechanism of miR-21-3p on intestinal injury and intestinal glycocalyx during fluid resuscitation in traumatic hemorrhagic shock (THS), and the different impacts of sodium lactate Ringer's solution (LRS) and sodium bicarbonate Ringer's solution (BRS) for resuscitation on intestinal damage. Methods : A rat model of THS was induced by hemorrhage from the left femur fracture. The pathological changes of intestinal tissues and glycocalyx structure were observed by hematoxylin-eosin staining and transmission electron microscope. MiR-21-3p expression in intestinal tissues was detected by real-time quantitative polymerase chain reaction. The expression of glycocalyx-, cell junction-, and PI3K/Akt/NF-κB signaling pathway-related proteins was analyzed by western blot. Results : MiR-21-3p expression was increased in THS rats, which was suppressed by resuscitation with BRS. BRS or LRS aggravated the intestinal injury and damaged intestinal glycocalyx in THS rats. The expression of SDC-1, HPA, β-catenin, MMP2, and MMP9 was upregulated, the expression of E-cad was downregulated, and the PI3K/Akt/NF-κB signaling pathway was activated in THS rats, which were further aggravated by BRS or LRS. The adverse effect of LRS was more serious than BRS. MiR-21-3p overexpression deteriorated the injury of intestinal tissues and intestinal glycocalyx; increased the expression of SDC-1, HPA, β-catenin, MMP2, and MMP9 while decreasing E-cad expression; and activated the PI3K/Akt/NF-κB signaling pathway in BRS-resuscitated THS rats. Conclusion : MiR-21-3p aggravated intestinal tissue injury and intestinal glycocalyx damage through activating PI3K/Akt/NF-κB signaling pathway in rats with THS resuscitated with BRS., (Copyright © 2024 by the Shock Society.)

Background: Avoiding missed diagnosis and therapeutic delay for significant blunt bowel and mesenteric injuries (sBBMIs) after trauma is still challenging despite the widespread use of computed tomography (CT). Several scoring tools aiming at reducing this risk have been published. The purpose of the present work was to assess the incidence of delayed (>24 hours) diagnosis for sBBMI patients and to compare the predictive performance of three previously published scores using clinical, radiological, and laboratory findings: the Bowel Injury Prediction Score (BIPS) and the scores developed by Raharimanantsoa Score (RS) and by Faget Score (FS)., Methods: A population-based retrospective observational cohort study was conducted; it included adult trauma patients after road traffic crashes admitted to Lausanne University Hospital, Switzerland, between 2008 and 2019 (n = 1,258) with reliable information about sBBMI status (n = 1,164) and for whom all items for score calculation were available (n = 917). The three scores were retrospectively applied on all patients to assess their predictive performance., Results: The incidence of sBBMI after road traffic crash was 3.3% (38 of 1,164), and in 18% (7 of 38), there was a diagnostic and treatment delay of more than 24 hours. The diagnostic performances of the FS, the RS, and the BIPS to predict sBBMI, expressed as the area under the receiver operating characteristic curve, were 95.3% (95% confidence interval [CI], 92.7-97.9%), 89.2% (95% CI, 83.2-95.3%), and 87.6% (95% CI, 81.8-93.3%) respectively., Conclusion: The present study confirms that diagnostic delays for sBBMI still occur despite the widespread use of abdominal CT. When CT findings during the initial assessment are negative or equivocal for sBBMI, using a score may be helpful to select patients for early diagnostic laparoscopy. The FS had the best individual diagnostic performance. However, the BIPS or the RS, relying on clinical and laboratory variables, may be helpful to select patients for early diagnostic laparoscopy when there are unspecific CT signs of bowel or mesenteric injury., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Abstract: Intestinal ischemia-reperfusion injury (IIRI) is a serious disease with high morbidity and mortality. This study aims to investigate the potential regulatory mechanisms involving protein arginine methyltransferase 6 (PRMT6), Forkhead box O3a (FoxO3a), and Parkin in IIRI and elucidate their roles in mediating cell apoptosis. The IIRI animal model was established and confirmed using hematoxylin and eosin staining. Oxygen-glucose deprivation and reperfusion (OGD/R) cell model was established to mimic ischemic injury in vitro . Transient transfection was used to overexpress or knock down genes. Cell death or apoptosis was assessed by propidium iodide staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and flow cytometry. The expression of proteins was detected by western blot. The histopathology observed by hematoxylin and eosin staining suggested that the IIRI animal model was successfully established. Our findings revealed that IIRI resulted in increased Bax and decreased Bcl-2 levels. In vitro experiments showed that overexpression of Parkin decreased OGD/R injury and suppressed elevation of Bax/Bcl-2. PRMT6 regulated the methylation level of FoxO3a. Moreover, FoxO3a directly binds to Parkin, and FoxO3a overexpression reduced OGD/R-induced cell death and regulation of Parkin. Overexpression of PRMT6 can attenuate the downregulation of Parkin and elevation of Bax/Bcl-2 caused by OGD/R. Knockdown of PRMT6 promoted apoptosis in intestinal epithelial cells of OGD/R group, while PRMT6 overexpression exhibited the opposite effect. Notably, the levels of PRMT6, FoxO3a, and Parkin were decreased in IIRI mouse intestinal tissue. Knocking out PRMT6 causes a significant decrease in the lifespan of mice. Altogether, our results demonstrated that PRMT6 upregulated the expression of Parkin by regulating FoxO3a methylation level, attenuating the apoptosis induced by IIRI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Purpose: Blunt bowel and/or mesenteric injury requiring surgery presents a diagnostic challenge. Although computed tomography (CT) imaging is standard following blunt trauma, findings can be nonspecific. Most studies have focused on the diagnostic value of CT findings in identifying significant bowel and/or mesenteric injury (sBMI). Some studies have described scoring systems to assist with diagnosis. Little attention, has been given to radiologist interpretation of CT scans. This study compared the discriminative ability of scoring systems (BIPS and RAPTOR) with radiologist interpretation in identifying sBMI., Methods: We conducted a retrospective chart review of trauma patients with suspected sBMI. CT images were reviewed in a blinded fashion to calculate BIPS and RAPTOR scores. Sensitivity and specificity were compared between BIPS, RAPTOR, and the admission CT report with respect to identifying sBMI., Results: One hundred sixty-two patients were identified, 72 (44%) underwent laparotomy and 43 (26.5%) had sBMI. Sensitivity and specificity were: BIPS 49% and 87%, AUC 0.75 (0.67-0.81), P < 0.001; RAPTOR 46% and 82%, AUC 0.72 (0.64-0.79), P < 0.001; radiologist impression 81% and 71%, AUC 0.82(0.75-0.87), P < 0.001. The discriminative ability of the radiologist impression was higher than RAPTOR (P = 0.04) but not BIPS (P = 0.13). There was not a difference between RAPTOR vs. BIPS (P = 0.55)., Conclusion: Radiologist interpretation of the admission CT scan was discriminative of sBMI. Although surgical vigilance, including evaluation of the CT images and patient, remains fundamental to early diagnosis, the radiologist's impression of the CT scan can be used in clinical practice to simplify the approach to patients with abdominal trauma., (© 2024. The Author(s).)

Foreign body ingestion of sharp objects can be a striking feature of psychological dysfunction with high morbidity and mortality. While the phenomenon has been reported on, primarily from a psychiatric perspective, this report will present the effects of this behavior on the intestinal system from a pathology perspective. The report is of a 43-year-old female with a past medical history of foreign object ingestion, borderline personality disorder, depression, anxiety, and prior suicidality who passed away due to bowel obstruction. Review of her history revealed an eighteen-year history of repeated foreign body ingestion with multiple surgical interventions. A particularly remarkable aspect revealed through the surgical history is the nature of the complications. They begin in 2008 with bowel perforation due to a blunt object and continue to present with perforation in the early years but show a gradual change to adhesions and obstruction as the primary concern. Her final presentation to the hospital and cause of death was due to obstruction, not perforation, even though the foreign bodies were six knives. While this case is not the only known report of foreign body ingestion, the extensive timeline and frequency allow for an examination of the gradual progression of fibrosis and adhesions within the intestines and abdominal wall, which led to the obstruction and death despite being a protective factor against further perforation.This case was presented at the annual Association of Clinical Scientists meeting (April 2-4, Jacksonville, FL)., (© 2024 by the Association of Clinical Scientists, Inc.)

Background: Primary aim was to assess the relative risk (RR) of anastomotic leak (AL) in intestinal bucket-handle (BH) compared to non-BH injury., Methods: Multi-center study comparing AL in BH from blunt trauma 2010-2021 compared to non-BH intestinal injuries. RR was calculated for small bowel and colonic injury using R., Results: AL occurred in 20/385 (5.2%) of BH vs. 4/225 (1.8%) of non-BH small intestine injury. AL was diagnosed 11.6 ± 5.6 days from index operation in small intestine BH and 9.7 ± 4.3 days in colonic BH. Adjusted RR for AL was 2.32 [0.77-6.95] for small intestinal and 4.83 [1.47-15.89] for colonic injuries. AL increased infections, ventilator days, ICU & total length of stay, reoperation, and readmission rates, although mortality was unchanged., Conclusion: BH carries a significantly higher risk of AL, particularly in the colon, than other blunt intestinal injuries., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Published by Elsevier Inc.)

Background: Sepsis is a dysregulated host response to infection syndrome leading to life-threatening organ dysfunction. Sepsis-induced intestinal dysfunction is a key element in the progression to multisystem organ failure. The stimulator of interferon genes is an intracellular protein implicated in intestinal injury in sepsis. H151, a small molecule inhibitor of stimulator of interferon genes, has not yet been studied as a potential therapeutic in sepsis. We hypothesize that H151 therapeutically reduces sepsis-induced acute intestinal injury., Methods: Male mice underwent cecal ligation and puncture and were treated with intraperitoneal H151 (10 mg/kg body weight) or vehicle. Intestines and serum were collected for analysis 20 hours after cecal ligation and puncture. Oral gavage of mice with FITC-dextran was performed 15 hours after cecal ligation and puncture. Five hours after gavage, serum was collected, and intestinal permeability was assessed. Mice were monitored for 10 days after cecal ligation and puncture to assess survival., Results: Zonula occludens 1 tight junctional protein expression was reduced after cecal ligation and puncture and recovered with H151 treatment. This was associated with a 62.3% reduction in intestinal permeability as assessed by fluorimetry. After cecal ligation and puncture, treatment with H151 was associated with a 58.7% reduction in intestinal histopathologic injury (P < .05) and a 56.6% reduction in intestinal apoptosis (P < .05). Intestinal myeloperoxidase activity was decreased by 70.8% after H151 treatment (P < .05). Finally, H151 improved 10-day survival from 33% to 80% after cecal ligation and puncture (P = .011)., Conclusion: H151, a novel stimulator of interferon genes inhibitor, reduces intestinal injury, inflammation, and permeability when administered as a treatment for cecal ligation and puncture-induced sepsis. Thus, targeting stimulator of interferon genes shows promise as a therapeutic strategy to ameliorate sepsis-induced acute intestinal injury., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The increasing applications of ionizing radiation in society raise the risk of radiation-induced intestinal and whole-body injury. Astaxanthin is a powerful antioxidant to reduce the reactive oxygen generated from radiation and the subsequent damage. However, the oral administration of astaxanthin remains challenging owing to its low solubility and poor bioavailability. Herein, we facilely construct an orally used microalgae-nano integrated system (SP@ASXnano) against radiation-induced intestinal and whole-body injury, combining natural microalgae Spirulina platensis (SP) with astaxanthin nanoparticles (ASXnano). SP and ASXnano show complementation in drug delivery to improve distribution in the intestine and blood. SP displays limited gastric drug loss, prolonged intestinal retention, constant ASXnano release, and progressive degradation. ASXnano improves drug solubility, gastric stability, cell uptake, and intestinal absorption. SP and ASXnano have synergy in many aspects such as anti-inflammation, microbiota protection, and fecal short-chain fatty acid up-regulation. In addition, the system is ensured with biosafety for long-term administration. The system organically combines the properties of microalgae and nanoparticles, which was expected to expand the medical application of SP as a versatile drug delivery platform.

We present the case of a man in his 30s who was crushed between two vehicles sustaining blunt trauma to his lower limbs and torso. The patient was in shock on arrival to the emergency department, and immediate resuscitation was given with massive transfusion protocol activation. Once the patient's haemodynamic status was stabilised, a CT scan revealed a complete colon transection. The patient was taken to the operating theatre where a midline laparotomy was performed, and the transected descending colon was managed with a segmental resection and handsewn anastomosis. The patient followed an unremarkable postoperative course, with bowels opening on day 8 postoperatively. Colon injuries are rare following blunt abdominal trauma, and a delay in diagnosis may lead to increased morbidity and mortality. As such, a low threshold for surgical intervention is recommended., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The impact of intestinal injury in cardiac arrest is not established. The first aim of this study was to assess associations between clinical characteristics in out-of-hospital cardiac arrest (OHCA) and a biomarker for intestinal injury, Intestinal Fatty Acid Binding Protein (IFABP). The second aim was to assess associations between IFABP and multiple organ dysfunction and 30-day mortality., Methods: We measured plasma IFABP in 50 patients at admission to intensive care unit (ICU) after OHCA. Demographic and clinical variables were analysed by stratifying patients on median IFABP, and by linear regression. We compared Sequential Organ Failure Assessment (SOFA) score, haemodynamic variables, and clinical-chemistry tests at day two between the "high" and "low" IFABP groups. Logistic regression was applied to assess factors associated with 30-day mortality., Results: Several markers of whole body ischaemia correlated with intestinal injury. Duration of arrest and lactate serum concentrations contributed to elevated IFABP in a multivariable model (p < 0.01 and p = 0.04, respectively). At day two, all seven patients who had died were in the "high" IFABP group, and all six patients who had been transferred to ward were in the "low" group. Of patients still treated in the ICU, the "high" group had higher total, renal and respiratory SOFA score (p < 0.01) and included all patients receiving inotropic drugs. IFABP predicted mortality (OR 16.9 per standard deviation increase, p = 0.04)., Conclusion: Cardiac arrest duration and lactate serum concentrations were risk factors for intestinal injury. High levels of IFABP at admission were associated with multiple organ dysfunction and mortality., Trial Registration: ClinicalTrials.gov: NCT02648061., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To develop a CT-based algorithm and evaluate its performance for the diagnosis of blunt bowel and/or mesenteric injury (BBMI) in patients with blunt abdominal trauma., Methods: This retrospective study included a training cohort of 79 patients (29 with BBMI and 50 patients with blunt abdominal trauma without BBMI) and a validation cohort of 37 patients (13 patients with BBMI and 24 patients with blunt abdominal trauma without BBMI). CT examinations were blindly analyzed by two independent radiologists. For each CT sign, the kappa value, sensitivity, specificity, and accuracy were calculated. A diagnostic algorithm was built using a recursive partitioning model on the training cohort, and its performances were assessed on the validation cohort., Results: CT signs with kappa value > 0.6 were extraluminal gas, hemoperitoneum, no or moderate bowel wall enhancement, and solid organ injury. CT signs yielding best accuracies in the training cohort were extraluminal gas (98%; 95% CI: 91-100), bowel wall defect (97%; 95% CI: 91-100), irregularity of mesenteric vessels (97%; 95% CI: 90-99), and mesenteric vessel extravasation (97%; 95% CI: 90-99). Using a recursive partitioning model, a decision tree algorithm including extraluminal gas and no/moderate bowel wall enhancement was built, achieving 86% sensitivity (95% CI: 74-99) and 96% specificity (95% CI: 91-100) in the training cohort and 92% sensitivity (95% CI: 78-97) and 88% specificity (95% CI: 74-100) in the validation cohort for the diagnosis of BBMI., Conclusions: An effective diagnostic algorithm was built to identify BBMI in patients with blunt abdominal trauma using only extraluminal gas and no/moderate bowel wall enhancement on CT examination., Key Points: • A CT diagnostic algorithm that included extraluminal gas and no/moderate bowel wall enhancement was built for the diagnosis of surgical blunt bowel and/or mesenteric injury. • A decision tree combining only two reproducible CT signs has high diagnostic performance for the diagnosis of surgical blunt bowel and/or mesenteric injury., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The inflammatory response induced by intestinal ischaemia‒reperfusion injury (I/R) is closely associated with infectious complications and mortality in critically ill patients, and the timely and effective clearance of apoptotic cells is an important part of reducing the inflammatory response. Studies have shown that the efferocytosis by phagocytes plays an important role. Recently, studies using small intestine organoid models showed that macrophage efferocytosis could promote the repair capacity of the intestinal epithelium. However, no studies have reported efferocytosis in the repair of I/R in animal models., Results: We used an in vivo efferocytosis assay and discovered that macrophage efferocytosis played an indispensable role in repairing and maintaining intestinal barrier function after I/R. In addition, the specific molecular mechanism that induced macrophage efferocytosis was Cth-ERK1/2 dependent. We found that Cth drove macrophage efferocytosis in vivo and in vitro. Overexpression/silencing Cth promoted/inhibited the ERK1/2 pathway, respectively, which in turn affected efferocytosis and mediated intestinal barrier recovery. In addition, we found that the levels of Cth and macrophage efferocytosis were positively correlated with the recovery of intestinal function in clinical patients., Conclusion: Cth can activate the ERK1/2 signalling pathway, induce macrophage efferocytosis, and thus promote intestinal barrier repair. Video Abstract., (© 2023. The Author(s).)

Percutaneous peritoneal dialysis catheter (PDC) insertion for continuous ambulatory peritoneal dialysis (CAPD) entails a higher risk of complications such as bowel injury, vascular injury, and catheter migration compared to the surgical insertions. We conducted a comparative analysis of two techniques of peritoneal entry for PDC insertion by Seldinger technique. We performed a retrospective review of 426 percutaneously inserted PDCs in nonobese naïve abdomens for CAPD at two tertiary care teaching hospitals in India over 6 years. Comparison of various mechanical complications, and short-term catheter survival was done between use of introducer needle (Group "I") and spring-loaded pneumoperitoneum (Veress) needle (Group "V"). Group "I" to "V" patient ratio was 277:149. Group "I" had heavier patients (p = 0.03) whereas "V" group had a dominance of diabetes (p = 0.009) and prior hemodialysis patients (p = 0.03). At 3 months, the odds of mechanical complications (OR = 0.27, p = 0.004), PDC migration (OR = 0.18, p = 0.02), and omental wrapping (OR = 0.13, p = 0.04) were less in "V" group. No bowel injury occurred with Veress needle use. At 6 months, "V" group had higher odds of event-free sustained PDC tip position (OR = 0.39, p = 0.003), and catheter survival (p = 0.03), and the cumulative events were lesser too (p = 0.002). Refractory peritonitis and deaths with functioning catheter were comparable between both the groups. In this first-of-its-kind study, spring-loaded Veress pneumoperitoneum needle use was safer, entrusted sustained PDC tip position in pelvis, and had a better catheter survival compared to use of introducer needle for peritoneal entry in percutaneously inserted PDCs. These findings should be confirmed by a randomized controlled study., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Introduction: Injuries to surrounding structures during radical prostatectomy (RP) are rare but serious complications. However, it remains unknown if injuries to intestines, rectum, or vascular structures occur at different rates depending on the surgical approach., Methods: We compared the frequency of these outcomes in open RP (ORP) and minimally invasive RP (MIS-RP) using the national American College of Surgeons National Surgical Quality Improvement Program database (2012-2017). Along with important metrics of clinical and surgical outcomes, patients were identified as undergoing surgical repair of small or large bowel, vascular structures, or hernias based on Current Procedural Terminology codes., Results: In our propensity matched analysis, a total of 13,044 patients were captured. Bowel injury occurred more frequently in ORP than in MIS-RP (0.89 vs. 0.26%, p < 0.01). By intestinal segment, rectal and large bowel injuries were more common in ORP than MIS-RP (0.41 vs. 0.11% and 0.31 vs. 0.05%, both p < 0.01). However, there was no statistically significant difference between the groups for small bowel injury (0.17 vs. 0.11%, p = 0.39). Vascular injury was more common in MIS-RP (0.18 vs. 0.08%, p = 0.08). Hernias requiring repair were only identified in the MIS-RP group (0.12%)., Conclusion: When considering surgical approach, rectal and large bowel injuries were more common in ORP, while vascular injuries and hernia repair were more common in MIS-RP. Our findings can be used in counseling patients and identifying risk factors and strategies to reduce these complications., (© 2021 S. Karger AG, Basel.)

The present study aimed to explore the protective effects of exogenous catalase (CAT) from microorganisms against lipopolysaccharide (LPS)-induced intestinal injury and its molecular mechanism in weaned pigs. Fifty-four weaned pigs (21 days of age) were randomly allocated to CON, LPS, and LPS+CAT groups. The pigs in CON and LPS groups were fed a basal diet, whereas the pigs in LPS+CAT group fed the basal diet with 2,000 mg/kg CAT supplementation for 35 days. On day 36, six pigs were selected from each group, and LPS and LPS+CAT groups were administered with LPS (50 μg/kg body weight). Meanwhile, CON group was injected with an equivalent amount of sterile saline. Results showed that LPS administration damaged intestinal mucosa morphology and barrier. However, CAT supplementation alleviated the deleterious effects caused by LPS challenge through enhancing intestinal antioxidant capacity which was benefited to decrease proinflammatory cytokines concentrations and suppress enterocyte apoptosis. Besides, LPS-induced gut microbiota dysbiosis was significantly shifted by CAT through decreasing mainly Streptococcus and Escherichia-Shigella. Our study suggested that dietary supplemented with 2,000 mg/kg catalase was conducive to improve intestinal development and protect against LPS-induced intestinal mucosa injury via enhancing intestinal antioxidant capacity and altering microbiota composition in weaned pigs. IMPORTANCE Exogenous CAT derived from microorganisms has been widely used in food, medicine, and other industries. Recent study also found that exogenous CAT supplementation could improve growth performance and antioxidant capacity of weaned pigs. However, it is still unknown that whether dietary exogenous CAT supplementation can provide a defense against the oxidative stress-induced intestinal damage in weaned pigs. Our current study suggested that dietary supplemented with 2,000 mg/kg CAT was conducive to improve intestinal development and protect against LPS-induced intestinal mucosa injury via enhancing intestinal antioxidant capacity and altering microbiota composition in weaned pigs. Moreover, this study will also assist in developing of CAT produced by microorganisms to attenuate various oxidative stress-induced injury or diseases.

Anastomotic leakage after intestinal resection is one of the most serious complications of surgical intervention for hollow viscus injury. Adequate vascular perfusion of the anastomotic site is essential to prevent anastomotic leakage. Near-infrared imaging using indocyanine green (NIR-ICG) is useful for the objective assessment of vascular perfusion. The aim of this study was to evaluate the association of NIR-ICG with intestinal and mesenteric injuries. This was a retrospective, single-center study of patients undergoing surgery for intestinal and mesenteric injuries. NIR-ICG was used to evaluate vascular perfusion. Postoperative complications were assessed between NIR-ICG and non-NIR-ICG groups.The use of NIR-ICG was associated with a lower incidence of Clavien-Dindo grade ≥ III complications with a statistical tendency (p = 0.076). When limited to patients that underwent intestinal resection, the use of NIR-ICG was significantly associated with a lower risk of perioperative complications (p = 0.009). The use of NIR-ICG tended to associate with the lower incidence of postoperative complications after intestinal and mesenteric trauma surgery. NIR-ICG was associated with a significantly lower risk of complications in patients undergoing intestinal resection. The NIR-ICG procedure is simple and quick and is expected to be useful for intestinal and mesenteric trauma., (© 2021. The Author(s).)

Remifentanil (RFT), extensively used for general anesthesia, is a synthetic ultra-short-acting opioid used as an anti-inflammatory oxidant to alleviate a plethora of diseases. This study was designed to determine whether RFT would provide protective effects on sepsis-induced intestinal injury.The determination of cell viability and inflammation of LPS-treated IEC-6 cells influenced by RFT was conducted by Cell counting Kit-8 (CCK-8), RT-qPCR, and western blot, while the detection of LDH, diamine oxidase (DAO), and intestinal-type fatty acid binding proteins (I-FABP) was conducted for determining the intestinal cytotoxicity in these cells. The apoptosis of these cells was detected by TUNEL, with autophagy-related protein expression measured by western blot to confirm whether autophagy was activated. Finally, the aforementioned assays were conducted again after 3-Methyladenine (3-MA), an autophagy inhibitor, was used on these cells to investigate whether RFT exerted its effects on LPS-treated IEC-6 cells via modulation of autophagy.RFT alleviates LPS-induced IEC-6 cell inflammation, cytotoxicity and apoptosis, and autophagy-related proteins were expressed at higher levels when RFT was used on these cells. Nevertheless, further treatment of 3-MA weakened the restorative impacts of RFT on the inflammation, cytotoxicity and apoptosis of these cells.To conclude, this paper is the first to present evidence that RFT attenuates sepsis-induced intestinal injury by inducing autophagy, which will provide instructions for the future investigations into the use of RFT in treatment of intestinal injury.

Background and Aim: The artificial sweetener acesulfame potassium (ACK) is officially approved as safe for intake and has been used in processed foods. However, ACKs have been reported to induce metabolic syndrome, along with alteration of the gut microbiota in mice. In recent years, studies have suggested that this artificial sweetener promotes myeloperoxidase reactivity in Crohn's disease-like ileitis. We aimed to investigate the effect of ACK on the intestinal mucosa and gut microbiota of normal mice., Methods: Acesulfame potassium was administered to C57BL/6J mice (8 weeks old) via free drinking. Intestinal damage was evaluated histologically, and messenger RNA (mRNA) levels of TNF-α, IFN-γ, IL1-β, MAdCAM-1, GLP1R, and GLP2R were determined with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed to examine the expression of MAdCAM-1 in the small intestine. The composition of gut microbiota was assessed using high-throughput sequencing. We performed intravital microscopic observation to examine if ACK altered lymphocyte migration to the intestinal microvessels., Results: Acesulfame potassium increased the expression of proinflammatory cytokines, decreased the expression of GLP-1R and GLP-2R, and induced small intestinal injury with an increase in intestinal permeability, and ACK treatment induced microbial changes, but the transfer of feces alone from ACK mice did not reproduce intestinal damage in recipient mice. ACK treatment significantly increased the migration of lymphocytes to intestinal microvessels., Conclusion: Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa. Massive use of non-caloric artificial sweeteners may not be as safe as we think., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Acute lung injury (ALI) carries a mortality rate of ~50% and is a hot topic in the world of critical illness research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical modulator of intracellular oxidative homeostasis and serves as an antioxidant. The Nrf2-related anti-oxidative stress is strongly associated with ferroptosis suppression. Meanwhile, telomerase reverse transcriptase (TERT), the catalytic portion of the telomerase protein, is reported to travel to the mitochondria to alleviate ROS. In our study, we found that TERT was significantly reduced in lung tissue of Nrf2 -/- mice in the model of intestinal ischemia/reperfusion-induced acute lung injury (IIR-ALI). In addition, MDA levels showed marked increase, whereas GSH and GPX4 levels fell drastically in ALI models. Moreover, typical-related structural changes were observed in the type II alveolar epithelial cells in the IIR model. We further employed the scanning transmission X-ray microscopy (STXM) to examine Fe levels and distribution within cells. Based on our observations, massive aggregates of Fe were found in the MLE-12 cells upon OGD/R (oxygen and glucose deprivation/reperfusion) induction. Additionally, Nrf2 silencing dramatically reduced TERT and SLC7A11 levels, and further exacerbated cellular injuries. In contrast, TERT-overexpressing cells exhibited marked elevation in SLC7A11 levels and thereby inhibited ferroptosis. Collectively, these data suggest that Nrf2 can negatively regulate ferroptosis via modulation of TERT and SLC7A11 levels. The conclusion from this study brings insight into new candidates that can be targeted in future IIR-ALI therapy., (© 2021. The Author(s).)

T-cells have been demonstrated to modulate ischemia-reperfusion injury (IRI) in the kidney, lung, liver, and intestine. Whereas most T-cell subpopulations contribute primarily to the antigen-specific effector and memory phases of immunity, γδ-T-cells combine adaptive features with rapid, innate-like responses that can place them in the initiation phase of immune reactions. Therefore, we aimed to clarify the role of γδ-T-cells in intestinal IRI. Adult wild-type (WT) and γδ-T-cell-deficient mice were subjected to acute intestinal IRI. Gene expression of pro-inflammatory cytokines and influx of leukocyte subpopulations in the gut were assessed by qPCR and flow cytometry. Serum transaminases were measured as an indicator of distant organ IRI. Intestinal IRI led to increased influx of neutrophils, pro-inflammatory cytokine expression and LDH/ALT/AST elevation. Selective deficiency of γδ-T-cells significantly decreased pro-inflammatory cytokine levels and neutrophil infiltration in the gut following IRI compared to controls. Furthermore, γδ-T-cell deficiency resulted in decreased LDH and transaminases levels in sera, indicating amelioration of distant organ injury. Increasing evidence demonstrates a key role of T-cell subpopulations in IRI. We demonstrate that γδ-T-cell deficiency ameliorated pro-inflammatory cytokine production, neutrophil recruitment and distant organ injury. Thus, γδ-T-cells may be considered as mediators contributing to the inflammatory response in the acute phase of intestinal IRI., (© 2021. The Author(s).)

Mesenteric ischemia and reperfusion (I/R) injury can ensue from a variety of vascular diseases and represents a major cause of morbidity and mortality in intensive care units. It causes an inflammatory response associated with local gut dysfunction and remote organ injury. Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of metabolic homeostasis. The catalytic α1 subunit is highly expressed in the intestine and vascular system. In loss-of-function studies, we investigated the biological role of AMPKα1 in affecting the gastrointestinal barrier function. Male knock-out (KO) mice with a systemic deficiency of AMPKα1 and wild-type (WT) mice were subjected to a 30 min occlusion of the superior mesenteric artery. Four hours after reperfusion, AMPKα1 KO mice exhibited exaggerated histological gut injury and impairment of intestinal permeability associated with marked tissue lipid peroxidation and a lower apical expression of the junction proteins occludin and E-cadherin when compared to WT mice. Lung injury with neutrophil sequestration was higher in AMPKα1 KO mice than WT mice and paralleled with higher plasma levels of syndecan-1, a biomarker of endothelial injury. Thus, the data demonstrate that AMPKα1 is an important requisite for epithelial and endothelial integrity and has a protective role in remote organ injury after acute ischemic events.

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin ( N -acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms.

OBJECTIVE. The objectives of this study were to examine the performance of CT in the diagnosis of ischemic mesenteric laceration after blunt trauma and to assess the predictive value of various CT signs for this injury. MATERIALS AND METHODS. In this retrospective study, consecutive patients with bowel and mesenteric injury diagnosed by CT or surgery from January 2011 through December 2016 were analyzed. Two radiologists evaluated CT images for nine signs of bowel injury. The outcome evaluated was ischemic mesenteric laceration. Univariable analysis followed by logistic regression was performed. RESULTS. The study included 147 patients (96 men and 51 women; median age, 35 years; age range, 23-52 years). Thirty-three patients had surgically confirmed ischemic mesenteric lacerations. CT signs that correlated with ischemic mesenteric laceration were abdominal wall injury, mesenteric contusion, free fluid, segmental bowel hypoenhancement, and bowel hyperenhancement adjacent to a hypoenhancing segment. The regression model developed after inclusion of clinical variables identified two predictors: segmental bowel hypoenhancement (adjusted odds ratio, 22.9 [95% CI, 7.9-66.2; p < .001] for reviewer 1 and 20.7 [95% CI, 7.2-59.0; p < .001] for reviewer 2) and abdominal wall injury (adjusted odds ratio, 5.26 [95% CI, 1.7-15.9; p = .003] for reviewer 1 and 5.3 [95% CI, 1.9-15.0; p = .002] for reviewer 2), which yielded an AUC of 0.87 for predicting injury. For reviewer 1 and reviewer 2, the sensitivities of CT in detecting the injury were 72.3% (95% CI, 54.5-86.7%) and 78.8% (95% CI, 61.0-91.0%), respectively, whereas the specificities were 94.7% (95% CI, 88.9-98.0%), and 92.1% (95% CI, 85.5-96.3%), respectively. CONCLUSION. CT has limited sensitivity but good specificity for detecting ischemic mesenteric laceration, with segmental bowel hypoenhancement considered the most predictive imaging sign.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia-reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10 min after the bleeding to maintain the intra-colon temperature at 37 °C (TRIC37°C group) or 12 °C (TRIC12°C group) for 270 min. The upper body temperature was maintained at as close to 37 °C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1/L-FABP, cardiac troponin I, and FABP2/I-FABP) were all drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-α, IL-1b, and IL-17F were also drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12°C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA. Amazingly, the mortality rate was 100% in TRIC37°C group whereas 0% in TRIC12°C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage.

Little is known about the ability for epithelial regeneration and wound healing in patients with inflammatory bowel diseases. We evaluated the epithelial proliferation and wound healing ability of patients with Crohn's disease (CD) using patient-derived intestinal organoids. Human intestinal organoids were constructed in a three-dimensional intestinal crypt culture of enteroscopic biopsy samples from controls and CD patients. The organoid-forming efficiency of ileal crypts derived from CD patients was reduced compared with those from control subjects ( p < 0.001). Long-term cultured organoids (≥6 passages) derived from controls and CD patients showed an indistinguishable microscopic appearance and culturing behavior. Under TNFα-enriched conditions (30 ng/mL), the organoid reconstitution rate and cell viability of CD patient-derived organoids were significantly lower than those of the control organoids ( p < 0.05 for each). The number of EdU+ cells was significantly lower in TNFα-treated organoids derived from CD patients than in TNFα-treated control organoids ( p < 0.05). In a wound healing assay, the unhealed area in TNFα-treated CD patient-derived organoids was significantly larger than that of TNFα-treated control organoids ( p < 0.001). The wound healing ability of CD patient-derived organoids is reduced in TNFα-enriched conditions, due to reduced cell proliferation. Epithelial regeneration ability may be impaired in patients with CD.

A novel bacteriocin secreted by Clostridium butyricum ZJU-F1 was isolated using ammonium sulfate fractionation, cation exchange chromatography, affinity chromatography, and reverse-phase high-performance liquid chromatography (RP-HPLC). The bacteriocin, named CBP22, contained 22 amino acids with the sequence PSAWQITKCAGSIAWALGSGIF. Analysis of its structure and physicochemical properties indicated that CBP22 had a molecular weight of 2264.63 Da and a +1 net charge. CBP22 showed activity against E. col K88 , E. coli ATCC25922 , and S. aureus ATCC26923 . The effects and potential mechanisms of bacteriocin CBP22 on the innate immune response were investigated with a lipopolysaccharide- (LPS-) induced mouse model. The results showed that pretreatment with CBP22 prevented LPS-induced impairment in epithelial tissues and significantly reduced serum levels of IgG, IgA, IgM, TNF- α , and sIgA. Moreover, CBP22 treatment increased the expression of the zonula occludens and reduced permeability as well as apoptosis in the jejunum in LPS-treated mice. In summary, CBP22 inhibits the intestinal injury and prevents the gut barrier dysfunction induced by LPS, suggesting the potential use of CBP22 for treating intestinal damage., Competing Interests: All authors declare that they have no conflict of interest., (Copyright © 2021 Tenghao Wang et al.)

Background: The incidence of small intestinal injury caused by low-dose aspirin (LDA) is high, but the pathogenesis and intervention measures of it have not been elucidated. Recent studies have found gut microbiota to be closely associated with onset and development of NSAID-induced intestinal injury. However, studies of the changes in the gut microbiota of rats with LDA-related intestinal injury have been lacking recently. In this study, we investigated fecal 16S rRNA gene sequencing analysis of changes in the gut microbiota of rats with LDA-related intestinal injury., Methods: Sprague-Dawley (SD) rat models of small intestinal injury were established by intragastric administration of LDA. The small intestinal tissues and the fecal samples were harvested. The fecal samples were then analyzed using high-throughput sequencing of 16S rRNA V3-V4 amplicons. The gut microbiota composition and diversity were analyzed and compared using principal coordinate analysis (PCoA), nonmetric multidimensional scaling (NMDS) analysis, the unweighted pair-group method with arithmetic mean (UPGMA) clustering analysis, multivariate statistical analysis (ANOSIM, MetaStats, and LEfSe), and spatial statistics., Results: The LDA rat model was successfully established. Decreased Firmicutes and increased Bacteroidetes abundances in rats with LDA-induced small intestinal injury were revealed. MetaStats analysis between the before administration of LDA (CG) and after administration of LDA (APC) groups showed that the intestinal floras exhibiting significant differences ( P < 0.05, q < 0.1) were Firmicutes, Bacteroides, Cyanobacteria, Melainabacteria, Coriobacteriia, Bacteroidia, Bacteroidales, Eubacteriaceae, and Streptococcaceae. In addition, the bacterial taxa showing significant differences between the control (NS) and APC groups were Firmicutes, Bacteroides, Verrucomicrobiaceae and Peptococcaceae., Conclusions: The alterations in the gut microbiota composition and diversity of rats with LDA-related intestinal injury were found in the present study. The change of gut microbiota in LDA-related intestinal injury will lay the foundation for further research on the function and signaling pathways of the intestinal flora and promote the use of intestinal flora as drug targets to treat LDA-induced small intestinal injury., Competing Interests: No potential conflict of interest was reported by the authors., (Copyright © 2021 Tianyu Chi et al.)

Severe ionizing radiation causes the acute lethal damage of haematopoietic system and gastrointestinal tract. Here, we found CL429, the novel chimeric TLR2/NOD2 agonist, exhibited significant radioprotective effects in mice. CL429 increased mice survival, protected mice against the lethal damage of haematopoietic system and gastrointestinal tract. CL429 was more effective than equivalent amounts of monospecific (TLR2 or NOD2) and combination (TLR2 + NOD2) of molecules in preventing radiation-induced death. The radioprotection of CL429 was mainly mediated by activating TLR2 and partially activating NOD2. CL429-induced radioprotection was largely dependent on the activation of TLR2-MyD88-NF-κB signalling pathway. In conclusion, the data suggested that the co-activation of TLR2 and NOD2 could induce significant synergistic radioprotective effects and CL429 might be a potential high-efficiency selective agent., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Intraoperative injuries during abdominopelvic surgery can be associated with substantial patient harm. The objective of this study was to describe abdominopelvic intraoperative injuries and their contributing factors among medicolegal cases., Methods: This study was a descriptive analysis of medicolegal matters reported to a national body, with subgroup analyses by type of surgery. We reviewed medicolegal matters involving a population-based sample of physicians who were subject to a civil legal action or complaint to a regulatory authority that was closed between 2013 and 2017 in Canada., Results: Our analysis included 181 civil legal cases and 88 complaints to a regulatory authority. Among legal cases, 155 patients (85.6%) (median age 47 yr) underwent elective procedures. The most common injury site was the bowel (53 cases [29.3%]). Injuries frequently occurred during dissection (79 [43.6%]) and ligation (38 [21.0%]), were identified postoperatively (138 [76.2%]) and necessitated further surgery (139 [76.8%]). Many patients experienced severe harm (55 [30.4%]) or died (25 [13.8%]). Peer experts in nongynecologic cases were more likely than those in gynecologic cases to include criticisms of a provider in a harmful incident (79 [71.2%] v. 30 [42.9%], p < 0.01). Peer expert criticisms often related to clinical evaluation, decision-making and misidentification of anatomy. Criticisms of nontechnical skills identified documentation and communication deficiencies., Conclusion: This study confirms the importance of provider and team training to improve clinical evaluation and decision-making, documentation and communication. Effective protocols may help support clinicians in providing safer surgical care., Competing Interests: Kirsten Devenny, Diane Héroux, Cara Bowman, Heather Neilson, Richard Mimeault and Lisa Calder are employees of the Canadian Medical Protective Association. Sukhbir Singh reports grants and personal fees from AbbVie, Bayer and Allergan, outside the submitted work. No other competing interests were declared., (© 2021 Joule Inc. or its licensors.)

The capacity of 3D organoids to mimic physiological tissue organization and functionality has provided an invaluable tool to model development and disease in vitro. However, conventional organoid cultures primarily represent the homeostasis of self-organizing stem cells and their derivatives. Here, we established a novel intestinal organoid culture system composed of 8 components, mainly including VPA, EPZ6438, LDN193189, and R-Spondin 1 conditioned medium, which mimics the gut epithelium regeneration that produces hyperplastic crypts following injury; therefore, these organoids were designated hyperplastic intestinal organoids (Hyper-organoids). Single-cell RNA sequencing identified different regenerative stem cell populations in our Hyper-organoids that shared molecular features with in vivo injury-responsive Lgr5 + stem cells or Clu + revival stem cells. Further analysis revealed that VPA and EPZ6438 were indispensable for epigenome reprogramming and regeneration in Hyper-organoids, which functioned through epigenetically regulating YAP signaling. Furthermore, VPA and EPZ6438 synergistically promoted regenerative response in gut upon damage in vivo. In summary, our results demonstrated a new in vitro organoid model to study epithelial regeneration, highlighting the importance of epigenetic reprogramming that pioneers tissue repair.

Background: Intestinal ostomy creation after trauma is selectively indicated for destructive colon and rectal injuries. However, the nationwide rates of creation of ostomies for trauma and their reversal are not known. The objective of this study was to ascertain national estimates of trauma ostomy creation and reversal., Methods: Weighted analysis of Healthcare Cost and Utilization Project Nationwide Readmissions Database 2014 to 2015 was performed. Adult trauma patients (≥16 years) with a hollow viscus injury were included. Patients with preexisting ostomies and permanent ostomies and those who died within 48 hours of admission were excluded. Rates of ostomy creation and same admission ostomy reversal were calculated. Rates of postdischarge ostomy reversal were calculated using the Kaplan-Meier estimator. Multivariable Cox proportional hazards model was used to determine factors associated with postdischarge trauma ostomy reversal., Results: A total of 22,542 patients sustained a hollow viscus injury resulting in the creation of 2,145 ostomies (9.6%). The rate of same-admission ostomy reversal was 0.7% (n = 16). At 1, 3, 6, and 9 months, the cumulative stoma reversal rates were 0%, 7.6%, 31.0%, and 43.1%, respectively. The mean ± SD time from ostomy creation to reversal was 123 ± 6.7 days for those undergoing reversal. Injury Severity Score greater than 9 was significantly associated with ostomy nonreversal after discharge (hazard ratio, 0.41; 95% confidence interval, 0.26-0.66). Age, sex, insurance status, penetrating injury, Charlson Comorbidity Index, and hospital teaching status were not significantly associated with ostomy reversal., Conclusion: The nationwide rate of ostomy creation after trauma is nearly 10%. At 6 months postinjury, only one third of patients had undergone ostomy reversal. Future study is needed to understand patient and provider-level factors associated with trauma ostomy reversal., Level of Evidence: Epidemiology, level III., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To establish common patterns of injury in vascular bowel and mesenteric injury (VBMI) and to identify any factors that may lead to delayed treatment., Methods and Materials: Forty-one patients with blunt VBMI presented to the level 1 trauma centre of the The Royal London Hospital over 5 years. Computed tomography (CT) images were reviewed to identify the specific location of injury and additional features such as seatbelt bruising and lumbar hernias. Surgical reports were reviewed to record any pertinent surgical findings at laparotomy., Results: The commonest mechanism of injury was a restrained car occupant involved in a road traffic collision (49%, n=20). The ileocaecal mesenteric vasculature was most frequently injured (41.5%, n=17), followed by the mid ileum (17.1%, n=7). Seatbelt bruising was identified in 80% of restrained car occupants and lumbar hernias in 22% of all patients with VBMI., Conclusion: Restrained car occupants involved in road traffic collisions are at increased risk of VBMI with particular susceptibility of the ileocaecal mesentery. This has implications for the reporting radiologist and trauma surgeon in deciding which patients require careful monitoring for the development of delayed bowel ischaemia., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Radiotherapy treatment-induced intestinal injury and gut microbial perturbation/dysbiosis have been implicated in the pathobiology of cancer-related fatigue. The objective of this brief review was to explore the available evidence of the relationship between intestinal injury and self-reported fatigue, especially among cancer patients. The scientific evidence-including our own-linking gut mucosal barrier dysfunction and gut microbial perturbation/dysbiosis induced by cancer treatment with worsening of cancer related fatigue (perhaps through the gut-brain axis) is limited but promising. Emerging data suggest that lifestyle interventions and the administration of specific probiotics may favorably modulate the gut microbiota and potentially mediate beneficial effects leading to improvements in fatigue.

Study Objective: To determine the feasibility of measuring hydrogen sulfide (H 2 S) gas in the insufflated abdomen during laparoscopic surgery after transmural bowel injury as a marker of unrecognized bowel injuries., Design: This is a feasibility study performed on swine models during a robotic training course. We aimed to determine baseline H 2 S levels and subsequent elevations in H 2 S levels after enterotomy of the large and small intestines., Setting: University-based robotic training lab., Participants: Three swine participants., Interventions: During initial insufflation of the swine abdominal cavity, baseline H 2 S levels were recorded over 15-second intervals for 10 minutes using the PortaSens II Portable Gas Leak Detector Model C16 (Analytical Technology, Inc., Collegeville, PA). The same values were recorded in separate studies after transmural transection of the small intestine and the large intestine using laparoscopic shears with and without monopolar electrosurgery., Measurements and Main Results: Baseline H 2 S level over the initial 10 minutes of insufflation was 0 parts per million (ppm). The device is calibrated to detect levels of H 2 S of 0 ppm to 200 ppm. H 2 S levels after small and large bowel enterotomies without monopolar electrosurgery initially showed a rise to 1 ppm to 2 ppm. However, repeat confirmatory testing failed to show any elevation in H 2 S levels. H 2 S levels after small and large bowel enterotomies with monopolar electrosurgery both showed increases to 108 ppm and 74 ppm with a duration of elevation measuring 4 minutes and 4 minutes 15 seconds, respectively. Although our study did show elevations in H 2 S after transection with monopolar electrosurgery, this was later determined to be the result of cross contamination with carbon monoxide, which was a confounding factor., Conclusion: Our study demonstrated that using the methodology and detection methods described, H 2 S cannot be used to detect unrecognized bowel injury during laparoscopic surgery. Our results were due to cross contamination with other gases created with the use of electrosurgery, and we were unable to reproduce initial testing results, which did show slight rises in H 2 S levels after enterotomies without monopolar electrosurgery. Further testing of other gases produced by the gastrointestinal tract or the use of alternative detection methods may provide more clinically relevant results., (Copyright © 2020. Published by Elsevier Inc.)

Regulatory mechanisms of microRNAs (miRNAs) in the development of intestinal sepsis are unclear. This study investigated the role of rno-miR-146b-5p in sepsis-induced intestinal injury. A rat sepsis model was created using the cecal ligation and puncture method. The expression profiles of miRNA and mRNA in sepsis rats were examined using miRNA and mRNA sequencing; rno-miR-146b was selected for further investigation. The mimics and inhibitors of rno-miR-146b-5p were transfected into IEC-6 cells and then with or without lipopolysaccharide (LPS) treatment, and the expressions of Kruppel-like factor 4 (Klf4) and Cyclin D2 (Ccnd2) were assessed by quantitative real-time transcriptase-polymerase chain reaction (qRT-PCR) and western blotting. Next, cell counting kit-8 assay was used to detect cell viability, and scratch wound healing assay was used to assess cell migration. In sepsis rat model, crypt cell proliferation was inhibited and crypt cell apoptosis was increased. Compared with the sham control, results of miRNA and mRNA sequencing showed that there were 17 miRNAs and 1617 mRNAs that were upregulated and 123 miRNAs and 1917 mRNAs that were downregulated in the sepsis model group. The network diagrams and qRT-PCR validation indicated that rno-miR-146b-5p may inhibit the expression of Klf4. By adjusting the expression of rno-miR-146b-5p in IEC-6 cells with or without LPS treatment, we found that increased expression of rno-miR-146b-5p inhibited cell proliferation and migration and inhibited the expression of Ccnd2. rno-miR-146b-5p may play a vital role in the development of sepsis intestinal injury through targeting Klf4 expression and affecting promoter activity of Ccnd2.

Radiation-induced multiorgan dysfunction is thought to result primarily from damage to the endothelial system, leading to a systemic inflammatory response that is mediated by the recruitment of leukocytes. The Eph-ephrin signaling pathway in the vascular system participates in various disease developmental processes, including cancer and inflammation. In this study, we demonstrate that radiation exposure increased intestinal inflammation via endothelial dysfunction, caused by the radiation-induced activation of EphA2, an Eph receptor tyrosine kinase, and its ligand ephrinA1. Barrier dysfunction in endothelial and epithelial cells was aggravated by vascular endothelial-cadherin disruption and leukocyte adhesion in radiation-induced inflammation both in vitro and in vivo. Among all Eph receptors and their ligands, EphA2 and ephrinA1 were required for barrier destabilization and leukocyte adhesion. Knockdown of EphA2 in endothelial cells reduced radiation-induced endothelial dysfunction. Furthermore, pharmacological inhibition of EphA2-ephrinA1 by the tyrosine kinase inhibitor dasatinib attenuated the loss of vascular integrity and leukocyte adhesion in vitro. Mice administered dasatinib exhibited resistance to radiation injury characterized by reduced barrier leakage and decreased leukocyte infiltration into the intestine. Taken together, these data suggest that dasatinib therapy represents a potential approach for the protection of radiation-mediated intestinal damage by targeting the EphA2-ephrinA1 complex.

Radiotherapy combined with chemotherapy is a common modality in abdominal cancer treatment. However, intestinal syndrome induced by radiation is a main factor leading to the poor prognosis of radiotherapy. In this work, we found that miR-378a-3p was markedly up-regulated in the small intestines of mice after total abdominal irradiation. Knocking-down (or overexpression) of miR-378a-3p increased (or decreased) the radiosensitivity of the small intestine cells HIEC and FHs-74-Int. Comet assay and γ-H2AX staining demonstrated that miR-378a-3p exerted its radioprotective function by reducing the accumulation of DNA damage in the cells and tissues of the small intestines. Mechanistically, miR-378a-3p could interact with the 3' UTR of CDK6 through complementary sequences and thus inhibited CDK6 expression in the small intestine cells. Rescue experiments suggested that the repression of miR-378a-3p overexpression on cell radiosensitivity and DNA damage accumulation was abrogated by the forced expression of CDK6. In summary, our results revealed for the first time that miR-378a-3p regulated the radiosensitivity and DNA damage response of small intestines by targeting CDK6. MiR-378a-3p may serve as a promising biomarker and radioprotective target in abdominal cancer., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Exaggerated Toll-like receptor (TLR) signaling and intestinal dysbiosis are key contributors to necrotizing enterocolitis (NEC). Lactobacillus rhamnosus GG (LGG) decreases NEC in preterm infants, but underlying mechanisms of protection remain poorly understood. We hypothesized that LGG alleviates dysbiosis and upregulates TLR inhibitors to protect against TLR-mediated gut injury., Methods: Effects of LGG (low- and high-dose) on intestinal pro-inflammatory TLR signaling and injury in neonatal mice subjected to formula feeding (FF) and NEC were determined. 16S sequencing of stool and expression of anti-TLR mediators SIGIRR (single immunoglobulin interleukin-1-related receptor) and A20 were analyzed., Results: FF induced mild intestinal injury with increased expression of interleukin-1β (IL-1β) and Kupffer cell (KC) (mouse homolog of IL-8) compared to controls. LGG decreased IL-1β and KC in association with attenuated TLR signaling and increased SIGIRR and A20 expression in a dose-dependent manner. Low- and high-dose LGG had varying effects on gut microbiome despite both doses providing gut protection. Subsequent experiments of LGG on NEC revealed that pro-inflammatory TLR signaling and intestinal injury were also decreased, and SIGIRR and A20 expression increased, in a dose-dependent manner with LGG pre-treatment., Conclusions: LGG protects against intestinal TLR-mediated injury by upregulating TLR inhibitors without major changes in gut microbiome composition.

Background and Objectives: The purpose of this study was to evaluate the incidence of small bowel obstruction (SBO) following hysterectomy and to identify factors that may increase the risk of SBO by route of hysterectomy., Methods: A retrospective review of the electronic medical records of all hysterectomies completed between January 2011 through July 2013 at our institution was performed. Information on patient demographics, comorbid conditions, and surgical characteristics were collected. All cases were reviewed for documentation of SBO in the immediate or remote postoperative period, up to 5 years post-hysterectomy., Results: Between January 2011 and July 2013, 1630 hysterectomies were performed at Montefiore Medical Center. A minimally invasive technique was employed for 49.8%, including 15.7% vaginal and 33.9% laparoscopic hysterectomies. Of these 1630 cases, 40 SBO's were documented; 30 after an abdominal approach and 10 after a minimally invasive approach. The overall incidence of SBO was 2.4%. A multivariable analysis adjusting for potential confounders demonstrated lower odds of SBO for the minimally invasive approaches combined, compared to abdominal hysterectomy (0.44, 95% confidence interval, 0.20, 0.98, p = .0444). Additional variables independently associated with development of SBO included intra-operative bowel injury and malignancy, whereas intra-operative blood loss and lysis of adhesions were not independently associated with SBO., Conclusions: After adjusting for confounders including malignancy, abdominal hysterectomy was associated with a significantly higher risk for SBO when compared to minimally invasive hysterectomy. Our study adds to the body of literature supporting a minimally invasive approach to hysterectomy when feasible., Competing Interests: Conflicts of Interest: none., (© 2020 by JSLS, Journal of the Society of Laparoscopic & Robotic Surgeons.)