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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., (© 2024. The Author(s).)

Background: Antimicrobial autoantigenic glycoprotein 2 (GP2) is an important component of the innate immune system which originates from the exocrine pancreas as well as from the small intestines. The relationship of GP2 with the intestinal microbiome as well as the systemic implications of increased fecal GP2 levels are, however, still unclear. Therefore, fecal samples from 2,812 individuals of the Study of Health in Pomerania (SHIP) were collected to determine GP2 levels (enzyme-linked immunosorbent assay) and gut microbiota profiles (16 S rRNA gene sequencing). These data were correlated and associated with highly standardised and comprehensive phenotypic data of the study participants., Results: Fecal GP2 levels were increased in individuals with higher body mass index and smokers, whereas lower levels were found in case of preserved exocrine pancreatic function, female sex or a healthier diet. Moreover, higher GP2 levels were associated with increased serum levels of high-sensitivity C-reactive protein, loss of gut microbial diversity and an increase of potentially detrimental bacteria (Streptococcus, Haemophilus, Clostridium XIVa, or Collinsella). At the same time, predicted microbial pathways for the biosynthesis of beneficial short-chain fatty acids or lactic acid were depleted in individuals with high fecal GP2. Of note, GP2 exhibited a stronger association to overall microbiome variation than calprotectin., Conclusion: Fecal GP2 is a biomarker of gut microbiota dysbiosis and associated with increased systemic inflammation. The intestines may be more important as origin for GP2 than pancreatic acinar cells. Future studies need to investigate the potential clinical value in disease specific patient cohorts., (© 2024. The Author(s).)

Background: Development of pancreatic necroses or pseudocysts are typical complications of pancreatitis and may require endoscopic drainage therapy using metal or plastic stents. Microbial infection of these lesions poses a major challenge. So far, the composition and significance of the microbial colonization on drainage stents are largely unknown although it may impact outcomes during endoscopic drainage therapy., Methods: A total of 26 stents used for drainage of pancreatic lesions were retrieved and the stent microbiome was determined by 16S rRNA gene sequencing. Additional analysis included comparison of the stent microbiome to the intracavitary necrosis microbiome as well as scanning electron microscopy (SEM) and micro-computed tomography (μCT) imaging of selected metal or plastic stents., Results: The stent microbiome comprises a large proportion of opportunistic enteric pathogens such as Enterococcus (14.4%) or Escherichia (6.1%) as well as oral bacteria like Streptococcus (13.1%). Increased levels of opportunistic enteric pathogens were associated with a prolonged hospital stay ( r  = 0.77, p  = 3e-06) and the occurrence of adverse events during drainage therapy ( p  = 0.011). Higher levels of oral bacteria were associated ( r  = -0.62, p  = 8e-04) with shorter durations of inpatient treatment. SEM and μCT investigations revealed complex biofilm networks on the stent surface., Conclusion: The composition of the stent microbiome is associated with prolonged hospital stays and adverse events during endoscopic drainage therapy, highlighting the need for effective infection control to improve patient outcomes. In addition to systemic antibiotic therapy, antimicrobial stent coatings could be a conceivable option to influence the stent microbiome and possibly enhance control of the necrotic microflora., 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 Frost, Khaimov, Senz, Weiss, Klußmann-Fricke, Rühlemann, Bang, Franke, Pickartz, Budde, Aghdassi, Siewert, Weiss, Grabow, Lerch and Sendler.)

Background: Anti-glycoprotein 2 (anti-GP2) IgA and antineutrophil-cytoplasmic antibodies to proteinase 3 (PR3-ANCA) have been reported as predictive markers of cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC), but their prevalence in CCA patients without PSC remains unclear., Methods: This study involved Asian discovery (n = 118) and European validation (n = 38) cohorts of CCA patients without PSC, alongside 49 Asian and 82 European pancreatic ductal adenocarcinoma (PDAC) patients, 21 with benign pancreatic neoplasms (BPN) and 45 with hepatocellular carcinoma (HCC), and 157 healthy controls (HC) from Asia and Europe. We analyzed the prevalence of PR3-ANCA, IgA and IgG against GP2 1 and GP2 4 , and the CA19-9 levels., Results: Anti-GP2 1 IgA was the most prevalent in both CCA cohorts (discovery: 55.1 %; validation: 42.1 %) and significantly higher than in other groups except PDAC (all p < 0.05). It demonstrated the best diagnostic performance in distinguishing CCA from disease controls and HC, outperforming tumor markers. No significant correlation was found between anti-GP2 1 IgA levels and CA19-9 levels., Conclusion: Our findings show that anti-GP2 1 IgA revealing the loss of mucosal tolerance is a potential novel diagnostic biomarker for CCA., Competing Interests: Declaration of competing interest Dirk Roggenbuck has ownership of Medipan and GA Generic Assays corporation stocks and profits earned from the stocks. The other authors declare that they have no conflicts of interest., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The co-localization of the lysosomal protease cathepsin B (CTSB) and the digestive zymogen trypsinogen is a prerequisite for the initiation of acute pancreatitis. However, the exact molecular mechanisms of co-localization are not fully understood. In this study, we investigated the role of lysosomes in the onset of acute pancreatitis by using two different experimental approaches. Using an acinar cell-specific genetic deletion of the ras-related protein Rab7, important for intracellular vesicle trafficking and fusion, we analyzed the subcellular distribution of lysosomal enzymes and the severity of pancreatitis in vivo and ex vivo. Lysosomal permeabilization was performed by the lysosomotropic agent Glycyl-L-phenylalanine 2-naphthylamide (GPN). Acinar cell-specific deletion of Rab7 increased endogenous CTSB activity and despite the lack of re-distribution of CTSB from lysosomes to the secretory vesicles, the activation of CTSB localized in the zymogen compartment still took place leading to trypsinogen activation and pancreatic injury. Disease severity was comparable to controls during the early phase but more severe at later time points. Similarly, GPN did not prevent CTSB activation inside the secretory compartment upon caerulein stimulation, while lysosomal CTSB shifted to the cytosol. Intracellular trypsinogen activation was maintained leading to acute pancreatitis similar to controls. Our results indicate that initiation of acute pancreatitis seems to be independent of the presence of lysosomes and that fusion of lysosomes and zymogen granules is dispensable for the disease onset. Intact lysosomes rather appear to have protective effects at later disease stages., (© 2024. The Author(s).)