American College of Gastroenterology Guidelines: Management of Acute Pancreatitis.

Acute pancreatitis (AP), defined as acute inflammation of the pancreas, is one of the most common diseases of the gastrointestinal tract leading to hospital admission in the United States. It is important for clinicians to appreciate that AP is heterogenous, progressing differently among patients and is often unpredictable. While most patients experience symptoms lasting a few days, almost one-fifth of patients will go on to experience complications, including pancreatic necrosis and/or organ failure, at times requiring prolonged hospitalization, intensive care, and radiologic, surgical, and/or endoscopic intervention. Early management is essential to identify and treat patients with AP to prevent complications. Patients with biliary pancreatitis typically will require surgery to prevent recurrent disease and may need early endoscopic retrograde cholangiopancreatography if the disease is complicated by cholangitis. Nutrition plays an important role in treating patients with AP. The safety of early refeeding and importance in preventing complications from AP are addressed. This guideline will provide an evidence-based practical approach to the management of patients with AP.

Fluid resuscitation in acute pancreatitis.

PURPOSE OF REVIEW: The purpose of the review is to critically evaluate the evidence from the literature to establish the current perspective on fluid resuscitation (FR) in acute pancreatitis (AP). We will review the rationale, type of fluid, rate of administration, total volume, duration, monitoring, ideal outcomes to be studied in clinical trials and recommendations for future studies. RECENT FINDINGS: FR remains the key component of supportive therapy in AP. The paradigm has shifted from administration of aggressive fluid resuscitation towards more moderate FR strategies. Lactated Ringer's remains the preferred fluid for resuscitation. There remain critical gaps in knowledge regarding the end point(s) to indicate adequate resuscitation, and accurate assessments of fluid sequestration and intravascular volume deficit in AP. SUMMARY: There is insufficient evidence to state that goal-directed therapy, using any of the parameters to guide fluid administration, reduces the risk of persistent organ failure, infected pancreatic necrosis, or mortality in AP, as well as the most appropriate method for the same.

In-person radiologist to review the trauma panscan: a high-fidelity simulation training program for radiology trainees at an academic level 1 trauma center.

BACKGROUND: Radiology trainees were uncomfortable going to the CT scanner to review trauma panscans and interacting with trauma surgeons. OBJECTIVE: This study aims to determine if radiology residents can be trained to accurately identify injuries requiring immediate surgical attention at the CT scanner. METHODS: A high-fidelity simulation model was created to provide an immersive training experience. Between February 2015 and April 2017, 62 class 1 trauma panscans were read at the CT scanner by 11 PGY-3 radiology residents. Findings made at the scanner were compared to resident preliminary and attending radiology reports and correlated with clinical outcomes. Timestamps were recorded and analyzed. Surveys were administered to assess the impact of training on radiology residents' self-confidence and to assess trauma surgeons' preference for radiology at the scanner. Significance level was set at p < 0.05. RESULTS: The mean time to provide results at the CT scanner was 11.1 min. Mean time for the preliminary report for CT head and cervical spine was 24.4 ± 9.8 min, and for the CT chest, abdomen, and pelvis was 16.3 ± 6.9 min. 53 traumatic findings on 62 panscans were identified at the scanner and confirmed at preliminary and final reports, for a concordance rate of 85%, compared to 72% for the control group. Radiology residents agreed or strongly agreed the training prepared them for trauma panscan reporting. Trauma surgeons shifted in favor of radiology presence at the scanner. CONCLUSION: Radiology residents can be trained to accurately and rapidly identify injuries requiring immediate surgical attention at the CT scanner. CLINICAL IMPACT: These findings support the value-added of an in-person radiologist at the CT scanner for whole-body trauma panscans to facilitate timely detection of life-threatening injuries and improve professional relations between radiologists and trauma surgeons.

Characteristics of 30-Day All-Cause Hospital Readmissions Among Patients with Acute Pancreatitis and Substance Use.

BACKGROUND/OBJECTIVES: Previous studies on healthcare resource utilization and 30-day readmission risks among patients with acute pancreatitis (AP) have focused upon opioid and alcohol use. The data on other substance types are lacking. In this study we aim to estimate the 30-day readmission rates, predictors of readmission, impact of readmission on patient outcomes and resulting economic burden among patients with AP and substance use in the USA. METHODS: This was a retrospective cohort study, based upon data from 2017 National Readmission Database of adult patients with AP and substance use (alcohol in combination, opioid, cannabis, cocaine, sedatives, other stimulants, other hallucinogens, other psychoactive, inhalant and miscellaneous). We estimated the 30-day readmission rates and predictors of 30-day readmission. RESULTS: Among 25,795 eligible patients, most were male, belonged to the lower income quartile, resided in the urban facility and had a Charlson comorbidity score of 0 or 1. The use of a combination of substances was the most common in 17,265 (66.9%) patients followed by only opioids in 4691 (18.2%) patients and only marijuana in 3839 (14.9%) patients. A total of 14.6% patients were readmitted within 30 days after discharge for non-elective causes with the highest risk of readmission within the 1st week after discharge with 5.2% readmissions. Among top ten causes of readmission, most of the principal diagnosis were related to AP in 53.1%. Compared to index admission, readmitted patients had significantly higher rates of acute cardiac failure, shock, and higher in-hospital mortality rate. Overall, readmission attributed to an additional 17,801 days of hospitalization resulting in a total of $150 million in hospitalization charges and $36 million in hospitalization costs in 2017. On multivariate analysis, chronic pancreatitis, self-discharge against medical advice, treatment at the highest volume centers, higher Charlson comorbidity index, increasing length of stay and severe disease were associated with higher odds of readmission while female gender and private insurance were associated with lower odds. CONCLUSION: Readmission was associated with higher morbidity and in-hospital mortality among patients with AP and substance use and resulted in a significant monetary burden on the US healthcare system. Several factors identified in this study may be useful for categorizing patients at higher risk of readmission warranting special attention during discharge planning.

Provider type influences adherence to lifestyle changes in chronic pancreatitis.

BACKGROUND: /Objectives: Alcohol and smoking cessation are recommended in chronic pancreatitis. The aim of this study is to measure the rates of alcohol and smoking cessation counselling among providers and adherence to recommendations. METHODS: Retrospective cohort study of chronic pancreatitis patients at a tertiary hospital. Provider types were defined as primary care (PCP), gastroenterologist, or pancreas specialist. Pairwise comparisons and multivariable analysis were conducted to assess the relation between provider type and smoking/alcohol cessation. RESULTS: Of 256 patients with chronic pancreatitis, 142 (55.5%) consumed alcohol and 130 (91.5%) were advised to stop. Alcohol cessation was advised to 88.9, 96.0 and 92.5% of patients followed by PCP, gastroenterologists and pancreas specialists, respectively. Sixty-one patients (46.9%) were compliant with the recommendation: 31.3, 44.0 and 54.1% of patients followed by PCP, gastroenterologists and pancreas specialists, respectively (Pairwise comparisons PCP vs Pancreas: p = 0.03, others nonsignificant). In multivariable analysis, patients followed by pancreas specialists were more likely to adhere to alcohol cessation recommendation compared to those followed by PCP (OR = 4.31, CI 1.52-12.20, p = 0.006). Smoking cessation was advised to all the 127 current smokers (100%). Fifty-six (44.1%) were compliant with the recommendation: 24.1, 58.3 and 47.3% of patients followed by PCP, gastroenterologists and pancreas specialists, respectively (Pairwise comparisons PCP vs Pancreas: p = 0.03, PCP vs. Gastroenterologist: p = 0.01, others nonsignificant). Multivariable analysis did not confirm this finding. CONCLUSIONS: The majority of providers counsel for alcohol/smoking cessation. Less than half the patients follow the recommendations. Patients followed by pancreas specialists were more likely to adhere to alcohol cessation recommendation.

Does Provider Type Affect Bone Health Surveillance in Chronic Pancreatitis?

BACKGROUND: Bone density screening (DEXA) and vitamin D serum assay (Vit-D) are recommended in chronic pancreatitis, but adherence by providers is unknown. AIMS: Assess DEXA/Vit-D testing according to provider type. METHODS: A retrospective cohort study of chronic pancreatitis patients followed in a tertiary hospital (August 2017-2018) was conducted. Provider type was primary care (PCP), gastroenterologist, and pancreas specialist. Chi-square test and multivariable analysis were conducted to assess the relation between provider type and DEXA/Vit-D testing. Subset analyses were performed among patients with fecal elastase < 200 mcg/g. RESULTS: A total of 478 charts were reviewed, and 256 (53.6%) met diagnosis of chronic pancreatitis; 184 (71.9%) definite, 45 (17.6%) probable, and 27 (10.6%) borderline chronic pancreatitis. DEXA was tested in 112/256 (43%) patients; 16/57(28%) patients followed by PCP, 11/38 (28.9%) by gastroenterologists, and 85/161(52.2%) by pancreas specialists (p = 0.001). Vit-D was tested in 210/256 (82.0%) patients; 42/57(73.7%) followed by PCP, 29/38 (76.3%) by gastroenterologists, and 139/161(86.3%) by pancreas specialists (p = 0.06). Multivariate analysis assessing DEXA/Vit-D testing showed pancreas specialists were more likely to test compared to PCP (DEXA: OR 3.70, CI 1.77-7.74, p = 0.001. Vit-D: OR 3.24, CI 1.43-7.38, p = 0.005), but gastroenterologists were not. In patients with low fecal elastase, pancreas specialists were more likely to test DEXA (pancreas specialists: 62.1%, PCP: 40.0%, Gastroenterologists: 11.1%, p = 0.01) and all patients received Vit-D testing. CONCLUSIONS: Chronic pancreatitis patients often do not receive optimal preventive care. Pancreas specialists were more likely to perform DEXA and Vit-D testing compared to PCP and gastroenterologists. More physician education is needed.

Hypertriglyceridemia and acute pancreatitis.

Hypertriglyceridemia is the third most common cause of acute pancreatitis. It typically occurs in patients with an underlying disorder of lipoprotein metabolism and in the presence of a secondary condition such as uncontrolled diabetes, alcohol abuse, or medication use. The presentation of hypertriglyceridemia-induced pancreatitis is similar to that of acute pancreatitis due to other causes; however, patients with hypertriglyceridemia-induced pancreatitis are more likely to have severe disease courses and have a higher likelihood of persistent organ failure. The initial treatment of hypertriglyceridemia-induced pancreatitis is also similar to acute pancreatitis from other causes and consists of aggressive fluid resuscitation, pain control, and nutritional support. Hypertriglyceridemia is specifically treated with apheresis or insulin therapy when necessary. The prompt recognition of hypertriglyceridemia in the setting of acute pancreatitis is essential in both the initial and long-term management of this disease and are essential to prevent recurrent acute pancreatitis. The review seeks to highlight the etiology, pathogenesis, and clinical course of hypertriglyceridemia-induced acute pancreatitis.

Opiate Prescriptions at Discharge Are Not Associated with Early Readmissions in Acute Pancreatitis.

BACKGROUND: Early readmissions in acute pancreatitis (AP) are common. The impact of opiate prescriptions on readmissions is unknown. AIMS: To determine whether the prescription of opiates at hospital discharge and the dose prescribed are associated with early readmissions in AP. METHODS: Direct admissions from the Emergency Department (ED) for AP from September 1, 2013, to August 31, 2016 were identified. Opiate prescription was defined as a new prescription at discharge in an opiate-naïve patient. Early readmission was ED visit or hospitalization within 30 days for an AP-related reason. Multivariable logistic regression was performed, adjusted for age, Charlson Comorbidity Index, pancreatic necrosis, baseline opiate use, non-opiate analgesics, and pain score at discharge. RESULTS: A total of 318 AP patients were identified; the overall early readmission rate was 18%. One hundred and twenty-one (38%) were prescribed opiates at discharge, and 22% had an early readmission. One hundred and ninety-seven (62%) were not prescribed opiates, and 16% had an early readmission. Median opiate dose was 48 mg (24-h morphine equivalents). On multivariable analysis, neither the prescription of opiates (OR 1.2, 95% CI 0.6-2.4, p = 0.55) nor the dose of opiates (OR 0.99, 95% CI 0.99-1.00, p = 0.39) was associated with early readmission. In subset analysis of patients discharged with an opiate prescription, those on opiates at baseline were significantly more likely to have an early readmission (OR 4.19, 95% CI 1.04-16.94, p = 0.04). CONCLUSIONS: In AP patients, neither prescription of opiates at discharge nor prescribed dose was associated with early readmission. Patients on opiates at baseline discharged with an opiate prescription were more likely to have an early readmission.

Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis.

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn's disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.

A clinical primer of the role of gut microbiome in health and disease.

Gut microbiome represents the total microbes present in the gastrointestinal tract including the genes they encode. These microbes primarily exist in a reciprocal state with the host contributing several important functions such as carbohydrates fermentation, vitamin biosynthesis and regulation of the immune system. The gut microbiome represents a dynamic organ, which responds to changes in the host, such as genetics and age, as well as environment such as diet and antibiotics. While these microbes can adapt to change, any disturbance in this host-microbe equilibrium has the potential to initiate a cascade of events leading to a disease phenotype. In this review we highlight the emerging role of gut microbiome in different gastrointestinal and systemic diseases, the role of current therapies and development of future therapies targeting the gut microbiome as a potential mode of treatment.

Marathon pancreatitis: a case of acute pancreatitis caused by distance running.

Marathon running or other forms of strenuous exercise have been reported as a rare cause of acute pancreatitis. Theories as to the mechanism of acute pancreatitis include microvascular ischaemia due to dehydration or repetitive trauma to the pancreas. We report a case of a healthy woman in her 30s who developed abdominal pain, nausea and vomiting after a 32 km marathon training run. She was found to have elevated lipase and inflammation of the pancreatic tail with associated pericolic and pelvic free fluid on CT scan. Workup including abdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP) did not reveal biliary or pancreatic duct pathology. She improved with conservative management. These findings support the hypothesis of exercise-induced pancreatitis from long-distance running.

Preliminary evidence of high prevalence of cerebral microbleeds in astronauts with spaceflight experience.

Long-duration spaceflight poses a variety of health risks to astronauts, largely resulting from extended exposure to microgravity and radiation. Here, we assessed the prevalence and incidence of cerebral microbleeds in sixteen astronauts before and after a typical 6-month mission on board the International Space Station Cerebral microbleeds are microhemorrhages in the brain, which are typically interpreted as early evidence of small vessel disease and have been associated with cognitive impairment. We identified evidence of higher-than-expected microbleed prevalence in astronauts with prior spaceflight experience. However, we did not identify a statistically significant increase in microbleed burden up to 7 months after spaceflight. Altogether, these preliminary findings suggest that spaceflight exposure may increase microbleed burden, but this influence may be indirect or occur over time courses that exceed 1 year. For health monitoring purposes, it may be valuable to acquire neuroimaging data that are able to detect the occurrence of microbleeds in astronauts following their spaceflight missions.

Evaluating implementation of a hospital-based cancer registry to improve childhood cancer care in low- and middle-income countries.

PURPOSE: Cancer is a leading cause of global childhood mortality, affecting 400,000 children annually. While treatable with modern therapies, children living in low- and middle-income countries (LMICs) have limited access to care and lower survival rates. Hospital-based cancer registries (HBCRs) collect detailed patient information to critically evaluate and evolve care. The St. Jude Global Childhood Cancer Analytics Resource and Epidemiological Surveillance System (SJCARES) is a cloud-based HBCR network facilitating quality data collection of pediatric cancer. Wide variation in the success of implementation has warranted further research into the implementation approach, to create a sustainable and adaptable HBCR in LMICs. METHODS: Seven of 89 sites using the SJCARES registry were selected, stratified by global region and stage of implementation. Semi-structured interviews were conducted with key groups (clinicians, administrators, data clerks) using an interview guide developed from the Consolidation Framework for Implementation Research (CFIR). Interviews were conducted via a video-telephone software program and transcribed by a transcription service. Transcripts were thematically coded using rapid qualitative analysis. RESULTS: A total of 18 participants (11 clinicians, 4 administrators, 3 data clerks) were interviewed. Several barrier themes were identified, including: difficulty integrating the registry into existing workflow; lack of resources; lack of government or administrative support; and damaged, misplaced, or illegible medical records. Facilitator themes were identified, including: internal support for the registry; clear and extensive training; and dedicated support staff. CONCLUSION: Interviewed participants identified key barriers and facilitators to the implementation of the SJCARES registry across multiple phases. We plan to use these results to develop targeted implementation strategies including a readiness assessment tool to help guide more successful implementation of the SJCARES registry and other HBCRs in LMICs.

Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice via suppressing aldo-keto reductase family 1B10 (AKR1B10).

Sulindac has been identified as a competitive inhibitor of aldo-keto reductase 1B10 (AKR1B10), an enzyme that plays a key role in carcinogenesis. AKR1B10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and exhibits lipid substrate specificity, especially for farnesyl and geranylgeranyl. There have been no studies though showing that the inhibition of PDAC by sulindac is via inhibition of AKR1B10, particularly the metabolism of farnesyl/geranylgeranyl and Kras protein prenylation. To determine the chemopreventive effects of sulindac on pancreatic carcinogenesis, 5-week-old LSL-Kras(G12D)-LSL-Trp53(R172H)-Pdx-1-Cre mice (Pan(kras/p53) mice) were fed an AIN93M diet with or without 200 p.p.m. sulindac (n = 20/group). Kaplan-Meier survival analysis showed that average animal survival in Pan(kras/p53) mice was 143.7 ± 8.8 days, and average survival with sulindac was increased to 168.0 ± 8.8 days (P < 0.005). Histopathological analyses revealed that 90% of mice developed PDAC, 10% with metastasis to the liver and lymph nodes. With sulindac, the incidence of PDAC was reduced to 56% (P < 0.01) and only one mouse had lymph node metastasis. Immunochemical analysis showed that sulindac significantly decreased Ki-67-labeled cell proliferation and markedly reduced the expression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Raf and mitogen-activated protein kinase kinase 1 and 2. In in vitro experiments with PDAC cells from Pan(kras/p53) mice, sulindac exhibited dose-dependent inhibition of AKR1B10 activity. By silencing AKR1B10 expression through small interfering RNA or by sulindac treatment, these in vitro models showed a reduction in Kras and human DNA-J homolog 2 protein prenylation, and downregulation of phosphorylated C-raf, ERK1/2 and MEK1/2 expression. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis by the inhibition of Kras protein prenylation by targeting AKR1B10.

Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency.

Soluble epoxide hydrolase (sEH) quickly inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) by converting them to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has shown effects against inflammation, but little is studied about the role of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study, the effect of sEH gene deficiency on the development of IBD-induced tumor development was determined in IL-10 knockout mice combined with sEH gene deficiency. Tumor development in the bowel was examined at the age of 25 wk for male mice and 35 wk for female mice. Compared to IL-10(-/-) mice, sEH (-/-)/IL-10(-/-) mice exhibited a significant decrease of tumor multiplicity (2 ± 0.9 tumors/mouse vs. 1 ± 0.3 tumors/mouse) and tumor size (344.55 ± 71.73 mm³ vs. 126.94 ± 23.18 mm³), as well as a marked decrease of precancerous dysplasia. The significantly lower inflammatory scores were further observed in the bowel in sEH(-/-)/IL-10(-/-) mice as compared to IL-10(-/-) mice, including parameters of inflammation-involved area (0.70 ± 0.16 vs. 1.4 ± 0.18), inflammation cell infiltration (1.55 ± 0.35 vs. 2.15 ± 0.18), and epithelial hyperplasia (0.95 ± 0.21 vs. 1.45 ± 0.18), as well as larger ulcer formation. qPCR and Western blotting assays demonstrated a significant downregulation of cytokines/chemokines (TNF-α, MCP-1, and IL-12, 17, and 23) and NF-κB signals. Eicosanoid acid metabolic profiling revealed a significant increase of ratios of EETs to DHETs and EpOMEs to DiOMEs. These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD.

Atorvastatin inhibits pancreatic carcinogenesis and increases survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mice.

There are several studies supporting the role of HMG-CoA reductase inhibitors such as atorvastatin against carcinogenesis, in which inhibiting the generation of prenyl intermediates involved in protein prenylation plays the crucial role. Mutation of Kras gene is the most common genetic alteration in pancreatic cancer and the Ras protein requires prenylation for its membrane localization and activity. In the present study, the effectiveness of atorvastatin against pancreatic carcinogenesis and its effect on protein prenylation were determined using the LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mouse model (called Pankras/p53 mice). Five-week-old Pankras/p53 mice were fed either an AIN93M diet or a diet supplemented with 100 ppm atorvastatin. Kaplan-Meier survival analysis with Log-Rank test revealed a significant increase in survival in mice fed 100 ppm atorvastatin (171.9 ± 6.2 d) compared to the control mice (144.9 ± 8.4 d, P < 0.05). Histologic and immunohistochemical analysis showed that atorvastatin treatment resulted in a significant reduction in tumor volume and Ki-67-labeled cell proliferation. Mechanistic studies on primary pancreatic tumors and the cultured murine pancreatic carcinoma cells revealed that atorvastatin inhibited prenylation in several key proteins, including Kras protein and its activities, and similar effect was observed in pancreatic carcinoma cells treated with farnesyltransferase inhibitor R115777. Microarray assay on the global gene expression profile demonstrated that a total of 132 genes were significantly modulated by atorvastatin; and Waf1p21, cyp51A1, and soluble epoxide hydrolase were crucial atorvastatin-targeted genes which involve in inflammation and carcinogenesis. This study indicates that atorvastatin has the potential to serve as a chemopreventive agent against pancreatic carcinogenesis.

CRISPR-Cas9 Long-Read Sequencing for Mapping Transgenes in the Mouse Genome.

Microinjected transgenes, both large and small, are known to insert randomly into the mouse genome. Traditional methods of mapping a transgene are challenging, thus complicating breeding strategies and accurate interpretation of phenotypes, particularly when a transgene disrupts critical coding or noncoding sequences. As the vast majority of transgenic mouse lines remain unmapped, we developed CRISPR-Cas9 Long-Read Sequencing (CRISPR-LRS) to ascertain transgene integration loci. This novel approach mapped a wide size range of transgenes and uncovered more complex transgene-induced host genome re-arrangements than previously appreciated. CRISPR-LRS offers a facile, informative approach to establish robust breeding practices and will enable researchers to study a gene without confounding genetic issues. Finally, CRISPR-LRS will find utility in rapidly and accurately interrogating gene/genome editing fidelity in experimental and clinical settings.

Soluble epoxide hydrolase gene deficiency or inhibition attenuates chronic active inflammatory bowel disease in IL-10(-/-) mice.

BACKGROUND: Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation. AIMS: To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(-/-) mice. METHODS: Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(-/-) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel. RESULTS: Compared to IL-10 (-/-) mice, sEH inhibition or sEH deficiency in IL-10(-/-) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB(4) and 5-HETE. CONCLUSION: These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (-/-) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.