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Gut Feb 2024Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP...
OBJECTIVE
Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission.
DESIGN
Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated.
RESULTS
After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP.
CONCLUSIONS
The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts.
TRIAL REGISTRATION NUMBER
NCT04777812.
Topics: Humans; Pancreatitis; Gastrointestinal Microbiome; Acute Disease; RNA, Ribosomal, 16S; Severity of Illness Index
PubMed: 38129103
DOI: 10.1136/gutjnl-2023-330987 -
Microbiology Spectrum Aug 2023The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung...
Mechanisms of Qingyi Decoction in Severe Acute Pancreatitis-Associated Acute Lung Injury via Gut Microbiota: Targeting the Short-Chain Fatty Acids-Mediated AMPK/NF-κB/NLRP3 Pathway.
The pivotal roles of gut microbiota in severe acute pancreatitis-associated acute lung injury (SAP-ALI) are increasingly revealed, and recent discoveries in the gut-lung axis have provided potential approaches for treating SAP-ALI. Qingyi decoction (QYD), a traditional Chinese medicine (TCM), is commonly used in clinical to treat SAP-ALI. However, the underlying mechanisms remain to be fully elucidated. Herein, by using a caerulein plus lipopolysaccharide (LPS)-induced SAP-ALI mice model and antibiotics (Abx) cocktail-induced pseudogermfree mice model, we tried to uncover the roles of the gut microbiota by administration of QYD and explored its possible mechanisms. Immunohistochemical results showed that the severity of SAP-ALI and intestinal barrier functions could be affected by the relative depletion of intestinal bacteria. The composition of gut microbiota was partially recovered after QYD treatment with decreased / ratio and increased relative abundance in short-chain fatty acids (SCFAs)-producing bacteria. Correspondingly increased levels of SCFAs (especially propionate and butyrate) in feces, gut, serum, and lungs were observed, generally consistent with changes in microbes. Western-blot analysis and RT-qPCR results indicated that the AMPK/NF-κB/NLRP3 signaling pathway was activated after oral administration of QYD, which was found to be possibly related to the regulatory effects on SCFAs in the intestine and lungs. In conclusion, our study provides new insights into treating SAP-ALI through modulating the gut microbiota and has prospective practical value for clinical use in the future. Gut microbiota affects the severity of SAP-ALI and intestinal barrier function. During SAP, a significant increase in the relative abundance of gut pathogens (Escherichia, , Enterobacter, , ) was observed. At the same time, QYD treatment decreased pathogenic bacteria and increased the relative abundance of SCFAs-producing bacteria (, , , , ). In addition, The AMPK/NF-κB/NLRP3 pathway mediated by SCFAs along the gut-lung axis may play an essential role in preventing the pathogenesis of SAP-ALI, which allows for reduced systemic inflammation and restoration of the intestinal barrier.
Topics: Mice; Animals; Pancreatitis; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; AMP-Activated Protein Kinases; Gastrointestinal Microbiome; Acute Disease; Prospective Studies; Acute Lung Injury; Fatty Acids, Volatile
PubMed: 37338348
DOI: 10.1128/spectrum.03664-22 -
Annals of Surgery Feb 2024To generate an up-to-date bundle to manage acute biliary pancreatitis using an evidence-based, artificial intelligence (AI)-assisted GRADE method.
The 2023 MANCTRA Acute Biliary Pancreatitis Care Bundle: A Joint Effort Between Human Knowledge and Artificial Intelligence (ChatGPT) to Optimize the Care of Patients With Acute Biliary Pancreatitis in Western Countries.
OBJECTIVE
To generate an up-to-date bundle to manage acute biliary pancreatitis using an evidence-based, artificial intelligence (AI)-assisted GRADE method.
BACKGROUND
A care bundle is a set of core elements of care that are distilled from the most solid evidence-based practice guidelines and recommendations.
METHODS
The research questions were addressed in this bundle following the PICO criteria. The working group summarized the effects of interventions with the strength of recommendation and quality of evidence applying the GRADE methodology. ChatGPT AI system was used to independently assess the quality of evidence of each element in the bundle, together with the strength of the recommendations.
RESULTS
The 7 elements of the bundle discourage antibiotic prophylaxis in patients with acute biliary pancreatitis, support the use of a full-solid diet in patients with mild to moderately severe acute biliary pancreatitis, and recommend early enteral nutrition in patients unable to feed by mouth. The bundle states that endoscopic retrograde cholangiopancreatography should be performed within the first 48 to 72 hours of hospital admission in patients with cholangitis. Early laparoscopic cholecystectomy should be performed in patients with mild acute biliary pancreatitis. When operative intervention is needed for necrotizing pancreatitis, this should start with the endoscopic step-up approach.
CONCLUSIONS
We have developed a new care bundle with 7 key elements for managing patients with acute biliary pancreatitis. This new bundle, whose scientific strength has been increased thanks to the alliance between human knowledge and AI from the new ChatGPT software, should be introduced to emergency departments, wards, and intensive care units.
Topics: Humans; Artificial Intelligence; Patient Care Bundles; Cholangiopancreatography, Endoscopic Retrograde; Pancreatitis, Acute Necrotizing; Acute Disease
PubMed: 37450700
DOI: 10.1097/SLA.0000000000006008 -
Renal Failure Dec 2023Acute pancreatitis (AP) is associated with a high incidence of acute kidney injury (AKI). This study aimed to develop a nomogram for predicting the early onset of AKI in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acute pancreatitis (AP) is associated with a high incidence of acute kidney injury (AKI). This study aimed to develop a nomogram for predicting the early onset of AKI in AP patients admitted to the intensive care unit.
METHOD
Clinical data for 799 patients diagnosed with AP were extracted from the Medical Information Mart for Intensive Care IV database. Eligible AP patients were randomly divided into training and validation cohorts. The independent prognostic factors for the early development of AKI in AP patients were determined using the all-subsets regression method and multivariate logistic regression. A nomogram was constructed for predicting the early occurrence of AKI in AP patients. The performance of the nomogram was evaluated based on the area under the receiver operating characteristic curve (AUC), calibration curves and decision curve analysis (DCA).
RESULTS
Seven independent prognostic factors were identified as predictive factors for early onset AKI in AP patients. The AUC of the nomogram in the training and validation cohorts were 0.795 (95% CI, 0.758-0.832) and 0.772 (95% CI, 0.711-0.832), respectively. The AUC of the nomogram was higher compared with that of the BISAP, Ranson, APACHE II scores. Further, the calibration curve revealed that the predicted outcome was in agreement with the actual observations. Finally, the DCA curves showed that the nomogram had a good clinical applicability value.
CONCLUSION
The constructed nomogram showed a good predictive ability for the early occurrence of AKI in AP patients.
Topics: Humans; Acute Kidney Injury; Databases, Factual; Pancreatitis; Retrospective Studies; Models, Statistical
PubMed: 36999227
DOI: 10.1080/0886022X.2023.2194436 -
Advanced Science (Weinheim,... Sep 2023Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis;...
Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.
Topics: Acinar Cells; Acute Disease; Adenosine Triphosphate; Bile Acids and Salts; Cell Hypoxia; Cellular Reprogramming; Extracellular Vesicles; Membrane Potential, Mitochondrial; Mesenchymal Stem Cells; Mitochondria; Mitochondrial Permeability Transition Pore; Pancreas; Pancreatitis; Paracrine Communication; Superoxides; Umbilical Cord; Humans
PubMed: 37409821
DOI: 10.1002/advs.202207691 -
Journal of Veterinary Internal Medicine 2023Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib...
BACKGROUND
Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib is a novel leukocyte function-associated antigen type-1 (LFA-1) activation inhibitor, blocking activation and subsequent adhesion and migration of neutrophils, potentially decreasing the risk of pancreatitis progression and systemic inflammation.
OBJECTIVE
Evaluate the safety and clinical response of dogs with AP after 3 days of administration of fuzapladib.
ANIMALS
Sixty-one client-owned dogs with presumptive AP.
METHODS
Randomized, masked, and placebo controlled multicenter study. Sixty-one dogs with AP were included for safety assessment, whereas 35 evaluable cases (fuzapladib, n = 16; placebo, n = 19) were included for clinical evaluation. Clinical improvement was assessed based on the change in the modified clinical activity index (MCAI) score on Day 3 compared to Day 0. Secondary variables included canine acute pancreatitis clinical severity index (CAPCSI) scores and serum concentrations of canine pancreatic lipase immunoreactivity, cytokines, and C-reactive protein.
RESULTS
Fuzapladib was well tolerated by all treated dogs. Mean change in MCAI scores was significantly higher in the fuzapladib-treated (-7.75) than the placebo group (-5.68; P = .02, 95% confidence interval [CI] for the difference, -4.33, -0.35), suggesting clinical improvement in fuzapladib-treated dogs. No significant difference was found in any of the secondary variables between groups.
CONCLUSIONS AND CLINICAL RELEVANCE
Administration of fuzapladib to dogs was safe, and a favorable response was detected in 2 clinical activity scores. Effects of fuzapladib on survival and duration of hospitalization were not studied.
Topics: Animals; Dogs; Acute Disease; C-Reactive Protein; Cytokines; Dog Diseases; Inflammation; Pancreatitis; Anti-Inflammatory Agents
PubMed: 37811705
DOI: 10.1111/jvim.16897 -
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 -
Molecular Medicine (Cambridge, Mass.) Oct 2023Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a...
BACKGROUND
Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4 T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis.
METHODS
The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed.
RESULTS
Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine.
CONCLUSION
Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.
Topics: Humans; Mice; Animals; Galantamine; alpha7 Nicotinic Acetylcholine Receptor; Acetylcholinesterase; Ceruletide; Acute Disease; Pancreatitis; Cytokines; Anti-Inflammatory Agents; Body Weight
PubMed: 37907853
DOI: 10.1186/s10020-023-00746-y -
Journal of Translational Medicine Feb 2024Acute pancreatitis and non-alcoholic fatty liver disease are both serious diseases in the digestive system. The pathogenesis of both diseases is extremely complex...
Exploring the interplay of gut microbiota, inflammation, and LDL-cholesterol: a multiomics Mendelian randomization analysis of their causal relationship in acute pancreatitis and non-alcoholic fatty liver disease.
BACKGROUND
Acute pancreatitis and non-alcoholic fatty liver disease are both serious diseases in the digestive system. The pathogenesis of both diseases is extremely complex closely and it related to gut microbiota, inflammation, and blood fat. There is a close relationship between gut microbiota and blood lipids.
METHODS
In this study, we used three types of exposure: 412 gut microbiota, 731 inflammatory cells, and 91 inflammatory proteins (pqtls), with LDL-C as an intermediary and acute pancreatitis and non-alcoholic fatty liver disease as outcomes. We mainly used MR-IVW, co-localization analysis, and reverse MR analysis methods for analysis.
RESULTS
7 gut microbiota, 21 inflammatory cells, and 3 inflammatory proteins can affect LDL-C levels. LDL-C is associated with acute pancreatitis and non-alcoholic fatty liver disease.
CONCLUSIONS
Three omics were used: 412 gut microbiota, 731 inflammatory cells, and 91 inflammatory proteins (pqtls). It explains the causal relationship between multiomics, LDL- cholesterol, acute pancreatitis, and non-alcoholic fatty liver disease.
Topics: Humans; Pancreatitis; Cholesterol, LDL; Gastrointestinal Microbiome; Acute Disease; Mendelian Randomization Analysis; Multiomics; Non-alcoholic Fatty Liver Disease; Inflammation; Genome-Wide Association Study
PubMed: 38374155
DOI: 10.1186/s12967-024-04996-0 -
Medicine Nov 2023Acute pancreatitis (AP) is one of the most common gastrointestinal diseases, and it is divided into 3 types according to its severity:mild acute pancreatitis, moderately... (Review)
Review
Acute pancreatitis (AP) is one of the most common gastrointestinal diseases, and it is divided into 3 types according to its severity:mild acute pancreatitis, moderately severe acute pancreatitis, and severe acute pancreatitis. The mortality in severe acute pancreatitis is approximately 15% to 30% due to multiorgan dysfunction and the lack of specific treatment. Interleukin-22 (IL-22) is a member of the Interleukin-10 family, and it can activate several downstream signaling pathways by binding to its receptor complex, thus it is involved in cell differentiation, proliferation, and apoptosis. Some studies have reported the elevated level of IL-22 in patients with AP, which suggests IL-22 may be involved in the pathogenesis of AP. And many studies have shown that IL-22 had a protective effect against AP. This article reviews the characteristics and mechanism of IL-22 and its role in AP to provide insight into the treatment of AP.
Topics: Humans; Pancreatitis; Acute Disease; Interleukin-6; Interleukins; Severity of Illness Index; Interleukin-22
PubMed: 37933011
DOI: 10.1097/MD.0000000000035695