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Duodenal dysbiosis may be potential infection risks in patients with severe acute pancreatitis (SAP). Acid-suppression drugs (ACDs) are widely used in SAP patients in Asian countries. However, the impact of ACDs on duodenal microbiota during the early phase of SAP is still unknown. This randomized controlled clinical trial evaluated the impacts of esomeprazole (Eso), one of ACDs on duodenal microbiota during the first week of SAP with duodenal aspirates culture and 16sRNA Illumina sequencing analysis. 66 patients were randomized as 1:1 ratio into Eso group (Eso 40 mg/day) and Eso-N group (no Eso). The occurrence of duodenal bacterial overgrowth (DBO) was significantly higher in Eso group (about 85%) than that in Eso-N group (about 42%). The duodenal microbiota of the SAP patients shifted away from that of the normal control. There were differences between the Eso-N and Eso groups including enriched abundances of the class Negativicutes, order Selenomonadales and genus Veillonella . Acid suppression significantly increased incidence of Candida oesophagitis (CE) by 8-folds but did not increase other infectious events. In conclusion, acid suppression greatly increased the occurrence of DBO, duodenal dysbiosis and CE during the first week of SAP. Restrictive use of acid-suppressing medications might be helpful to reduce CE and potential risk of pancreatic infection in SAP patients. Trial registration : Chictr.org, ChiCTR-IPR-16008301, Registered April 18 2016, http://www.chictr.org.cn/showproj.aspx?proj=14089 .

The exocrine pancreas is the main source of digestive enzymes which are released from secretory vesicles of acinar cells into the small intestine. Enzymes, including amylases, proteases and lipases, degrade the ingested food and thus determine the nutritional substrate for the gut microbiota. Acute (AP) and chronic pancreatitis (CP) are associated with a transitional or progressive exocrine pancreatic dysfunction, we analysed in the present study how an experimental induction of pancreatitis in mouse models affects the colonic and duodenal microbiome composition. Evaluation by 16 S rRNA gene sequencing revealed specific microbiome changes in colonic as well as in duodenal samples in different models of AP and CP. Mild acute pancreatitis, which is associated with a transient impairment of pancreatic secretion showed only minor changes in microbial composition, comparable to the ones seen in progressive dysfunctional mouse models of CP. The strongest changes were observed in a mouse model of severe AP, which suggest a direct effect of the immune response on gut microbiome in addition to a pancreatic dysfunction. Our data indicate that highly dysbiotic microbiome changes during pancreatitis are more associated with the inflammatory reaction than with a disturbed pancreatic secretion.

Background Chronic pancreatitis is a risk factor for pancreatic cancer. Autoimmune pancreatitis is a unique form of chronic pancreatitis that is primarily characterized by its immune mediate etiology, clinically resembling pancreatic cancer, yet uniquely responsive to steroid treatment. Objective Early and accurate diagnosis of autoimmune pancreatitis is vital for effective treatment and patient prognosis, for which new diagnostic tools are urgently required. Gut microbiota dysbiosis has been identified to correlate with the development of pancreatic diseases, which provides new opportunities for the discovery of disease biomarkers. Methods We utilized a mass spectrometric global metabolomics investigation of patient autoimmune pancreatitis and chronic pancreatitis fecal samples, investigating microbiome, dietary and human metabolism. Results We discovered a series of newly identified metabolic signatures between both patient groups including enterolactone, 4‐guanidinobutanoic acid, and methylthioadenosine sulfoxide. Additionally, the analysis revealed significant differences in several metabolic pathways such as fatty acids, alkaloids, amino acids and peptides. Conclusion Our observations provide novel insights into important metabolic human pathways and microbiome‐derived metabolites to distinguish autoimmune pancreatitis from chronic pancreatitis. These findings reveal systemic metabolic responses and the identified metabolites may be developed into potential biomarkers for future diagnosis to distinguish between autoimmune pancreatitis and chronic pancreatitis.

Objective: To study the effect of the Lactobacillus plantarum (LP) enteral feeding on the gut permeability and sepsis in the patients with acute pancreatitis. Subjects: Seventy-six subjects who stayed over 1 week in the hospital completed the study. Subjects were not treated with any lactobacillus supplement before the intervention. Methods: Seventy-six patients with acute pancreatitis were randomly divided into two groups, parenteral nutrition (PN) group (n=38) and ecoimmunonutrition (EIN) group supplied by LP enteral feeding (n=36). The acute physiology and chronic health evaluation score, Balthazar CT score, CRP, fecal bacterial species and DNA fingerprint profiles as well as the potentially pathologenic organisms in nasogastric aspirate were determined on the day of admission and on the 8 day. The intestinal permeability was assessed by measurement of the ratio of lactulose/rhamnose on the day of admission and on days 5 and 8. The rate of organ failure, septic complications and death cases were evaluated at the 8 day. Results: Following 7 days treatment, 38.9% patients in the EIN group were colonized with multiple organisms compared to 73.7% in the PN group (P<0.01), and 30.6% patients in the EIN grew potentially pathogenic organisms compared to 50% patients in PN group (P<0.05). The fecal bacterial DNA fingerprint profiles were less, the amount of lactobacteria and bifydobacteria decreased, and the amount of enterococci increased in PN group as compared with EIN group, P<0.05. By day 8, the lactulose/rhamnose ratio in EIN group were lower than that in PN group at days 5 and 8, P<0.05. The patients with LP got a better clinical outcomes as compared with the patients with PN. Conclusion: EIN enteral feeding can attenuate disease severity, improve the intestinal permeability and clinical outcomes.

Background Infected necrosis complicates 10% of all acute pancreatitis episodes and is associated with 15–20% mortality. The current standard treatment for infected necrotizing pancreatitis is the step-up approach (catheter drainage, followed, if necessary, by minimally invasive necrosectomy). Catheter drainage is preferably postponed until the stage of walled-off necrosis, which usually takes 4 weeks. This delay stems from the time when open necrosectomy was the standard. It is unclear whether such delay is needed for catheter drainage or whether earlier intervention could actually be beneficial in the current step-up approach. The POINTER trial investigates if immediate catheter drainage in patients with infected necrotizing pancreatitis is superior to the current practice of postponed intervention. Methods POINTER is a randomized controlled multicenter superiority trial. All patients with necrotizing pancreatitis are screened for eligibility. In total, 104 adult patients with (suspected) infected necrotizing pancreatitis will be randomized to immediate (within 24 h) catheter drainage or current standard care involving postponed catheter drainage. Necrosectomy, if necessary, is preferably postponed until the stage of walled-off necrosis, in both treatment arms. The primary outcome is the Comprehensive Complication Index (CCI), which covers all complications between randomization and 6-month follow up. Secondary outcomes include mortality, complications, number of (repeat) interventions, hospital and intensive care unit (ICU) lengths of stay, quality-adjusted life years (QALYs) and direct and indirect costs. Standard follow-up is at 3 and 6 months after randomization. Discussion The POINTER trial investigates if immediate catheter drainage in infected necrotizing pancreatitis reduces the composite endpoint of complications, as compared with the current standard treatment strategy involving delay of intervention until the stage of walled-off necrosis. Trial registration ISRCTN, 33682933 . Registered on 6 August 2015. Retrospectively registered.

Results of a previous randomized multicenter trial involving 102 patients with severe acute pancreatitis treated with or without adjuvant selective decontamination (SD) were analyzed additionally with regard to the bacteriologic status of (peri)pancreatic necrosis. The incidence of gramnegative pancreatic infection was significantly reduced in patients treated with SD (P = .004). Once such an infection develops, mortality increases 15-fold (P < .001) in comparison with that for patients with sterile necrosis. Among patients in whom only gram-positive infection of pancreatic necrosis was found, there was no significant increase in mortality. These results were similar in both treatment groups. In addition, the hospital stay was significantly longer in cases of gramnegative infected necrosis. The incidence of gram-positive infected necrosis in patients treated with SD did not increase. Gram-negative pancreatic infection can be prevented with adjuvant SD, thereby reducing mortality among patients with severe acute pancreatitis.

Diseases intrinsic to the pancreas such as pancreatitis, pancreatic cancer and type 1 diabetes mellitus impart substantial health and financial burdens on society but identification of novel mechanisms contributing to these pathologies are slow to emerge. A novel area of research suggests that pancreatic-specific disorders might be modulated by the gut microbiota, either through a local (direct pancreatic influence) or in a remote (nonpancreatic) fashion. In this Perspectives, we examine literature implicating microorganisms in diseases of the pancreas, specifically pancreatitis, type 1 diabetes mellitus and pancreatic ductal adenocarcinoma. We also discuss evidence of an inherent pancreatic microbiota and the influence of the intestinal microbiota as it relates to disease association and development. In doing so, we address pitfalls in the current literature and areas of investigation that are needed to advance a developing field of research that has clinical potential to reduce the societal burden of pancreatic diseases.

BackgroundThe gut is implicated in the pathogenesis of acute pancreatitis (AP) and the infectious complications of AP are commonly associated with enteric bacteria, yet whether gut microbiota dysbiosis participants in AP severity remains largely unknown.MethodsWe collected clinical information and fecal samples from 165 adult participants, including 41 with mild AP (MAP), 59 with moderately severe AP (MSAP), 30 with severe AP (SAP) and 35 healthy controls (HC). The serum inflammatory cytokines and gut barrier indexes were detected. Male C57BL/6 mice with AP were established and injuries of pancreas were evaluated in antibiotic-treated mice, germ-free mice as well as those transplanted with fecal microbiota. The gut microbiota was analyzed by 16S rRNA gene sequencing.ResultsThe structure of gut microbiota was significantly different between AP and HC, and the disturbed microbiota was closely correlated with systematic inflammation and gut barrier dysfunction. Notably, the microbial composition changed further with the worsening of AP and the abundance of beneficial bacteria such as Blautia was decreased in SAP compared with MAP and MSAP. The increased capacity for the inferred pathway, bacterial invasion of epithelial cells in AP, highly correlated with the abundance of Escherichia–Shigella. Furthermore, the antibiotic-treated mice and germ-free mice exhibited alleviated pancreatic injury after AP induction and subsequent fecal microbiota transplantation in turn exacerbated the disease.ConclusionsThis study identifies the gut microbiota as an important mediator during AP and its dysbiosis is associated with AP severity, which suggests its role as potential therapeutic target.

Background The endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a pro-inflammatory mediator in various inflammatory disorders. However, the function and underlying mechanism of heparanase in acute pancreatitis remain poorly understood. Here, we investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis. Methods Acute pancreatitis was induced in wild-type and heparanase-transgenic mice by administration of caerulein. The differences in gut microbiota were analyzed by 16S ribosomal RNA sequencing. Antibiotic cocktail experiment, fecal microbiota transplantation, and cohousing experiments were used to assess the role of gut microbiota. Results As compared with wild-type mice, acute pancreatitis was exacerbated in heparanase-transgenic mice. Moreover, the gut microbiota differed between heparanase-transgenic and wild-type mice. Heparanase exacerbated acute pancreatitis in a gut microbiota-dependent manner. Specially, the commensal Parabacteroid es contributed most to distinguish the differences between wild-type and heparanase-transgenic mice. Administration of Parabacteroides alleviated acute pancreatitis in wild-type and heparanase-transgenic mice. In addition, Parabacteroides produced acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration. Conclusions The gut–pancreas axis played an important role in the development of acute pancreatitis and the acetate produced by Parabacteroides may be beneficial for acute pancreatitis treatment. AXqtS6bvN-oakcGDurjdFQ Video abstract

Summary Despite improvements in surgical treatment and intensive care, mortality from severe acute pancreatitis remains high. We have carried out a randomised study of 60 consecutive patients with alcohol-induced necrotising pancreatitis to find out whether early antibiotic treatment can improve outcome. 30 patients were assigned cefuroxime (4·5 g/day intravenously) from admission. In the second group, no antibiotic treatment was given until clinical or microbiologically verified infection or after a secondary rise in C-reactive protein. The inclusion criteria were C-reactive protein concentration above 120 mg/L within 48 h of admission and low enhancement (<30 Hounsfield units) on contrast-enhanced computed tomography. There were more infectious complications in the non-antibiotic than in the antibiotic group (mean per patient 1·8 vs 1·0, p=0·01). The most common cause of sepsis was Staphylococcus epidermidis; positive cultures were obtained from pancreatic necrosis or the central venous line in 14 of 18 patients with suspected but blood-culture-negative sepsis. Mortality was higher in the non-antibiotic group (seven vs one in the antibiotic group; p=0·03). Four of the eight patients who died had cultures from pancreatic necrosis positive for Staph epidermidis. We conclude that cefuroxime given early in necrotising pancreatitis is beneficial and may reduce mortality, probably by decreasing the frequency of sepsis.