Role of SCO-792, A Novel Enteropeptidase Inhibitor, In the Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

Acute pancreatitis is the most common iatrogenic dilemma of endoscopic retrograde cholangiopancreatography, and it is associated with significant morbidity and mortality. Several factors have been implicated in the pathogenesis of post-endoscopic retrograde cholangiopancreatography pancreatitis, and preventive measures were practiced accordingly. This study aims to refine the potential mechanisms that trigger post-endoscopic retrograde cholangiopancreatography pancreatitis and define the role of enteropeptidase in the pathogenesis of post-endoscopic retrograde cholangiopancreatography pancreatitis. Furthermore, address the role of a new novel medication known as SCO-792, a potent enteropeptidase inhibitor, in the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.Post-endoscopic retrograde cholangiopancreatography pancreatitis is caused by premature activation of the pancreatic enzymes within the pancreatic parenchyma. This activation is either an autoactivation due to direct provocation of intra-acinar enzymes as a result of the procedure or due to activation by enterpeptidase, a rate-limiting enzyme. Endoscopic retrograde cholangiopancreatography interjects duodenal juice that is rich in enterokinase into the pancreatic-biliary tract, which in turn leads to intra-ductal activation of trypsinogen and subsequent enzymes. Given the vital role of enterokinase in initiating the pathogenesis of pancreatitis, enteropeptidase inhibition may prevent and reduce the severity of post-endoscopic retrograde cholangiopancreatography pancreatitis.SCO-792, a novel enteropeptidase inhibitor, is developed by SCOHIA Pharma, and pre-clinical trials confirmed its efficacy in inhibiting enteropeptidase. Studies are needed to confirm the efficacy of enteropeptidase inhibitors in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis.

Enterococcus spp. have higher fitness for survival, in a pH-dependent manner, in pancreatic juice among duodenal bacterial flora

Objectives: Bacterial infection is involved in the progression of many gastrointestinal diseases, including cancer; however, how and which bacteria colonize in pancreatic juice and tissue have yet to be elucidated. Recently, we reported that Enterococcus faecalis exists in the pancreatic juice and tissues of patients with chronic pancreatic disease. Here, we investigated the survival of E. faecalis in duodenal juice with different pH conditions. Methods: Pancreatic juice samples from 62 patients with cancers of the duodeno-pancreato-biliary region were evaluated for the presence of E. faecalis. 16S ribosomal RNA PCR and 16S-based metagenome analyses were performed to determine the bacterial composition. The survival of E. faecalis in various pancreatic juice conditions was evaluated. Results: Of 62 samples, 27% (17/62) were positive for Enterococcus spp., among which 71% (12/17) contained E. faecalis. Enterococcus spp. showed the highest fitness for survival in alkaline pancreatic juice among various bacterial species. The microbiome of pancreatic juice from patients with pancreatic and bile duct cancer showed diversity, but Enterococcus spp. were enriched among duodenal tumors and intraductal papillary mucinous neoplasms. Conclusions: Alkalinity is important for the selective survival of E. faecalis among microbiota. E. faecalis may induce pancreatic inflammation with changes in pancreatic juice conditions.

Biliary Microbiota in Choledocholithiasis and Correlation With Duodenal Microbiota

BackgroundThe pathogenesis of choledocholithiasis is closely related to the role of bacteria. However, little is known about the predictive role of bile bacteria in clinical conditions of patients and the compositional and functional characteristics of biliary microbiota in choledocholithiasis.MethodsTo investigate the predictive value of biliary bacteria, clinical data of 488 patients with choledocholithiasis were collected. The predictive value of common bile bacteria to patients’ clinical conditions was analyzed by logistic regression. Samples of bile and corresponding duodenal juice from 10 selected patients with choledocholithiasis were obtained, and the composition and function of microbial communities were analyzed based on 16S rRNA sequencing and Tax4Fun.ResultsThe clinical conditions of patients with choledocholithiasis, such as recurrence, the severity of acute cholangitis, and duration of hospital stay were closely related to different species of bile bacteria as well as antimicrobial-resistant bacteria. Employing 16S rRNA sequencing, the dominant phyla of biliary and duodenal microbiota were Proteobacteria and Firmicutes. The top three core microbiota at the genus level were Escherichia–Shigella, Fusobacterium, and Enterococcus. Escherichia coli accounted for the most abundant annotated species in both. Differences in composition between biliary and duodenal microbiota were not significant according to the alpha and beta diversities. Differential abundant features were not found in biliary microbiota indicated by A linear discriminant analysis effective size algorithm. The major pathways identified in biliary and duodenal microbiota were related to membrane transport, translation, replication and repair, carbohydrate and amino acid metabolism. However, no significant difference in those major pathways, as well as antimicrobial-resistance patterns, was observed between biliary and duodenal microbiota.ConclusionOur study first demonstrates the predictive contribution of biliary bacteria to the clinical conditions of patients with choledocholithiasis, and then it offers new insights into the compositional and functional features of biliary and duodenal microbiota. Similarities between biliary and duodenal microbiota support the theory of bacterial duodenal–biliary reflux in patients with choledocholithiasis. Meanwhile, when it is impracticable to obtain a bile sample, duodenal juice may be used as an alternative for bacterial culture and susceptibility tests.

Analysis of the relationship between bile duct and duodenal microbiota reveals that dysbacteriosis is the main cause of primary common bile duct stones

Background Bacteria play an important role in the formation of primary CBD stones. While the composition and function of the microbiota of bile duct in patients with primary CBD stones could not be explained in the whole. Intestinal dysbacteriosis is related to the formation of many diseases, but there are relatively few reports on the effects of intestinal microbial community on the formation of primary CBD stones, but none of these studies have a normal population of biliary tract and gut microbiota as control.Result We use the 16S rRNA gene high-throughput sequencing technology to analyze the microbial diversity and community composition of biliary and duodenal microbiota in 15 patients with primary CBD stones (EG) and 4 patients without biliary tract disease (CK), and we divided above samples into four subgroups: B (EG bile), D (EG duodenal juice), BCK (CK bile)and DCK (CK duodenal juice). Alpha diversity analysis showed that only the abundance and evenness in B were lower than that in DCK (P<0.05); Beta diversity analysis showed that there were some differences in the composition between biliary microbiota and the duodenal microbiota, but the abundance of the main groups showed similarities. Proteobacteria and Firmicutes were the dominant bacteria at phylum level accounted for at least 75% of the total reads in each subgroup. It is noteworthy that Clostridium sensu_stricto (VIP>1), Lachnospiraceae _UCG-008 (VIP>1), Butyrivibrio (VIP>1) and Roseburia (VIP> 1) which could produce short chain fatty acids (SCFA), were significantly decreased in B (p<0.05) than that in BCK. Conclusion According to the results, dysbacteriosis of biliary and duodenal microbiota plays an important role in the formation of primary CBD stones. The decrease in abundance of certain major acid-producing bacteria affects the health of the biliary tract and thus leads to the formation of stones.

Digestion-on-a-chip: a continuous-flow modular microsystem recreating enzymatic digestion in the gastrointestinal tract

A three-compartment, miniaturized system to pretreat samples with artificial saliva, gastric juice, duodenal juice and bile for gut-on-a-chip applications.

The Combination of MiRNA-196b, LCN2, and TIMP1 is a Potential Set of Circulating Biomarkers for Screening Individuals at Risk for Familial Pancreatic Cancer

Individuals at risk (IAR) of familial pancreatic cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were analyzed in 218 individuals with sporadic pancreatic ductal adenocarcinoma (PDAC, n = 50), FPC (n = 20), chronic pancreatitis (n = 10), IAR with relevant precursor lesions (n = 11) or non-relevant lesions (n = 5), 20 controls, and IAR with (n = 51) or without (n = 51) lesions on pancreatic imaging. In addition, corresponding duodenal juice samples were analyzed for Glypican-1 (n = 144) enrichment and KRAS mutations (n = 123). The panel miR-196b/LCN2/TIMP1 could distinguish high-grade lesions and stage I PDAC from controls with absolute specificity and sensitivity. In contrast, Glypican-1 enrichment in serum exosomes and duodenal juice was not diagnostic. KRAS mutations in duodenal juice were detected in 9 of 12 patients with PDAC and only 4 of 9 IAR with relevant precursor lesions. IAR with lesions on imaging had elevated miR-196b/LCN2/TIMP1 levels (p = 0.0007) and KRAS mutations in duodenal juice (p = 0.0004) significantly more often than IAR without imaging lesions. The combination miR-196b/LCN2/TIMP1 might be a promising biomarker set for the detection of high-grade PDAC precursor lesions in IAR of FPC families.