Abstract
BackgroundThe 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.MethodsAcute 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.ResultsAs 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 Parabacteroides 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.ConclusionsThe 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-oakcGDurjdFQVideo abstract
Highlights
Acute pancreatitis (AP) is a common disease that manifests as acute abdominal pain and involves pancreatic enzyme activation and pancreatic “self-digestion”
Acute pancreatitis was exacerbated in Heparanase transgenic (Hpa-Tg) mice First, we found that compared with the control mice, the overall Hpa mRNA level was significantly higher in AP mice (Fig. 1a)
The results showed that Parabacteroides abundance notably changed in Antibiotic cocktail (ABX), fecal microbiota transplantation (FMT) and cohousing experiments, which was consistent with AP phenotype changes in these group (Figure S7b-d, compared to Figure S3, Figs. 3 and 4)
Summary
Acute pancreatitis (AP) is a common disease that manifests as acute abdominal pain and involves pancreatic enzyme activation and pancreatic “self-digestion”. The endoglycosidase heparanase (Hpa) degrades heparan sulfate (HS) proteoglycans. Hpa has been identified as a pro-inflammatory mediator in various inflammatory disorders, such as rheumatoid arthritis [5], Barrett’s esophagus [6], Crohn’s disease [7], ulcerative colitis [8], and sepsis [9]. Hpa overexpression is observed in human chronic pancreatitis [10]. In AP, Hpa inhibitor PG545 alleviates pancreatic inflammation in mice [11]. The specific mechanism by which Hpa promotes AP remains unclear. The endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a proinflammatory mediator in various inflammatory disorders. The function and underlying mechanism of heparanase in acute pancreatitis remain poorly understood. We investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis
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