Abstract
Hypertriglyceridemia (HTG) aggravates the course of acute pancreatitis (AP). Intestinal barrier dysfunction is implicated in the pathogenesis of AP during which dysbiosis of intestinal microbiota contributes to the dysfunction in intestinal barrier. However, few studies focus on the changes in intestine during HTG-related acute necrotizing pancreatitis (ANP). Here, we investigated the changes in intestinal microbiota and Paneth cell antimicrobial peptides (AMPs) in HTG-related ANP (HANP) in rats. Rats fed a high-fat diet to induce HTG and ANP was induced by retrograde injection of 3.5% sodium taurocholate into biliopancreatic duct. Rats were sacrificed at 24 and 48 h, respectively. Pancreatic and ileal injuries were evaluated by histological scores. Intestinal barrier function was assessed by plasma diamine oxidase activity and D-lactate level. Systemic and intestinal inflammation was evaluated by tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-17A expression. 16S rRNA high throughput sequencing was used to investigate changes in intestinal microbiota diversity and structure. AMPs (α-defensin5 and lysozyme) expression was measured by real-time polymerase chain reaction (PCR) and immunofluorescence. The results showed that compared with those of normal-lipid ANP (NANP) groups, the HANP groups had more severe histopathological injuries in pancreas and distal ileum, aggravated intestinal barrier dysfunction and increased TNFα, IL-1β, and IL-17A expression in plasma and distal ileum. Principal component analysis showed structural segregation between the HANP and NANP group. α-Diversity estimators in the HANP group revealed decreased microbiota diversity compared with that in NANP group. Taxonomic analysis showed dysbiosis of intestinal microbiota structure. In the HANP group, at phyla level, Candidatus_Saccharibacteria and Tenericutes decreased significantly, whereas Actinobacteria increased. At genus level, Allobaculum, Bifidobacterium, and Parasutterella increased significantly, while Alloprevotella, Anaerotruncus, Candidatus_Saccharimonas, Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, Ruminiclostridium_5, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-014 decreased. Compared with those in the NANP rats, mRNA expression of lysozyme and α-defensin5 and protein expression of lysozyme decreased significantly in the HANP rats. Moreover, in the NANP rats and the HANP rats, Allobaculum abundance was inversely correlated with lysozyme expression, while Anaerotruncus abundance was positively correlated with it by Spearman test. In conclusion, intestinal microbiota dysbiosis and decreased AMPs of Paneth cells might participate in the pathogenesis of intestinal barrier dysfunction in HANP.
Highlights
Hypertriglyceridemia (HTG) is a well-established risk factor for acute pancreatitis (AP)
In all acute necrotizing pancreatitis (ANP) rats, the pancreatic injuries were featured by extensive enlarged interlobular interspaces, patchy necrosis, hemorrhage, and inflammatory cell infiltration
The injuries in pancreas had higher histopathological scores in the HTG-related ANP (HANP) groups than those in the normal-lipid ANP (NANP) groups (p < 0.05).We found the histopathological changes in distal ileum including shortened villi, edema, and infiltration of inflammatory cells in rats with ANP
Summary
Hypertriglyceridemia (HTG) is a well-established risk factor for acute pancreatitis (AP). Clinical studies reported that acute necrotizing pancreatitis (ANP) patients with HTG suffered a more severe clinical course and complications including infection, sepsis, and multiple organ failure. The animal experiments gave the evidences that HTG with AP could exaggerate pancreatic and systemic inflammatory response (Ponzo et al, 2006; Zeng et al, 2012; Zheng et al, 2016). It has not been fully elucidated how the HTG influences and deteriorates the course of AP. Few studies focus on the alteration of intestinal microbiota in HTG-related ANP (HANP)
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