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Gut Jul 2023In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death....
OBJECTIVE
In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the T/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.
DESIGN
AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (T) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed T activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.
RESULTS
The prophylactic Tdepletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8/γδTCR IELs. T depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa which associates with severe disease and infected necrosis was diminished in T depleted animals.
CONCLUSION
T play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, T-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting T in AP may help to ameliorate the disease course.
Topics: Mice; Humans; Animals; T-Lymphocytes, Regulatory; Pancreatitis, Acute Necrotizing; Acute Disease; Bacterial Translocation; RNA, Ribosomal, 16S; Mice, Inbred C57BL
PubMed: 36631247
DOI: 10.1136/gutjnl-2022-327448 -
Gastroenterology Nov 2023Exocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes... (Review)
Review
DESCRIPTION
Exocrine pancreatic insufficiency (EPI) is a disorder caused by the failure of the pancreas to deliver a minimum/threshold level of specific pancreatic digestive enzymes to the intestine, leading to the maldigestion of nutrients and macronutrients, resulting in their variable deficiencies. EPI is frequently underdiagnosed and, as a result, patients are often not treated appropriately. There is an urgent need to increase awareness of and treatment for this condition. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review was to provide Best Practice Advice on the epidemiology, evaluation, and management of EPI.
METHODS
This Expert Review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: EPI should be suspected in patients with high-risk clinical conditions, such as chronic pancreatitis, relapsing acute pancreatitis, pancreatic ductal adenocarcinoma, cystic fibrosis, and previous pancreatic surgery. BEST PRACTICE ADVICE 2: EPI should be considered in patients with moderate-risk clinical conditions, such as duodenal diseases, including celiac and Crohn's disease; previous intestinal surgery; longstanding diabetes mellitus; and hypersecretory states (eg, Zollinger-Ellison syndrome). BEST PRACTICE ADVICE 3: Clinical features of EPI include steatorrhea with or without diarrhea, weight loss, bloating, excessive flatulence, fat-soluble vitamin deficiencies, and protein-calorie malnutrition. BEST PRACTICE ADVICE 4: Fecal elastase test is the most appropriate initial test and must be performed on a semi-solid or solid stool specimen. A fecal elastase level <100 μg/g of stool provides good evidence of EPI, and levels of 100-200 μg/g are indeterminate for EPI. BEST PRACTICE ADVICE 5: Fecal elastase testing can be performed while on pancreatic enzyme replacement therapy. BEST PRACTICE ADVICE 6: Fecal fat testing is rarely needed and must be performed when on a high-fat diet. Quantitative testing is generally not practical for routine clinical use. BEST PRACTICE ADVICE 7: Response to a therapeutic trial of pancreatic enzymes is unreliable for EPI diagnosis. BEST PRACTICE ADVICE 8: Cross-sectional imaging methods (computed tomography scan, magnetic resonance imaging, and endoscopic ultrasound) cannot identify EPI, although they play an important role in the diagnosis of benign and malignant pancreatic disease. BEST PRACTICE ADVICE 9: Breath tests and direct pancreatic function tests hold promise, but are not widely available in the United States. BEST PRACTICE ADVICE 10: Once EPI is diagnosed, treatment with pancreatic enzyme replacement therapy (PERT) is required. If EPI is left untreated, it will result in complications related to fat malabsorption and malnutrition, having a negative impact on quality of life. BEST PRACTICE ADVICE 11: PERT formulations are all derived from porcine sources and are equally effective at equivalent doses. There is a need for H2 or proton pump inhibitor therapy with non-enteric-coated preparations. BEST PRACTICE ADVICE 12: PERT should be taken during the meal, with the initial treatment of at least 40,000 USP units of lipase during each meal in adults and one-half of that with snacks. The subsequent dosage can be adjusted based on the meal size and fat content. BEST PRACTICE ADVICE 13: Routine supplementation and monitoring of fat-soluble vitamin levels are appropriate. Dietary modifications include a low-moderate fat diet with frequent smaller meals and avoiding very-low-fat diets. BEST PRACTICE ADVICE 14: Measures of successful treatment with PERT include reduction in steatorrhea and associated gastrointestinal symptoms; a gain of weight, muscle mass, and muscle function; and improvement in fat-soluble vitamin levels. BEST PRACTICE ADVICE 15: EPI should be monitored and baseline measurements of nutritional status should be obtained (body mass index, quality-of-life measure, and fat-soluble vitamin levels). A baseline dual-energy x-ray absorptiometry scan should be obtained and repeated every 1-2 years.
Topics: Exocrine Pancreatic Insufficiency; Humans; Gastroenterology; Enzyme Replacement Therapy; Pancreatic Function Tests; Risk Factors; United States; Societies, Medical
PubMed: 37737818
DOI: 10.1053/j.gastro.2023.07.007