Systemic Bile Acids Affect the Severity of Acute Pancreatitis in Mice Depending on Their Hydrophobicity and the Disease Pathogenesis

Abstract

Acute pancreatitis (AP) is a major, globally increasing gastrointestinal disease and a biliary origin is the most common cause. However, the effects of bile acids (BAs), given systemically, on the pancreas and on disease severity remains elusive. In this study, we have investigated the roles of different circulating BAs in animal models for AP to elucidate their impact on disease severity and the underlying pathomechanisms. BAs were incubated on isolated acini and AP was induced through repetitive injections of caerulein or L-arginine; pancreatic duct ligation (PDL); or combined biliopancreatic duct ligation (BPDL). Disease severity was assessed using biochemical and histological parameters. Serum cholecystokinin (CCK) concentrations were determined via enzyme immunoassay. The binding of the CCK1 receptor was measured using fluorescence-labeled CCK. In isolated acini, hydrophobic BAs mitigated the damaging effects of CCK. The same BAs further enhanced pancreatitis in L-arginine- and PDL-based pancreatitis, whereas they ameliorated pancreatic damage in the caerulein and BPDL models. Mechanistically, the binding affinity of the CCK1 receptor was significantly reduced by hydrophobic BAs. The hydrophobicity of BAs and the involvement of CCK seem to be relevant in the course of AP. Systemic BAs may affect the severity of AP by interfering with the CCK1 receptor.

Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis

“…Quang et al. 19 showed that different types of bile acids exhibited different effects in different animal models of AP. For example, hydrophilic bile acids, represented by TLCS, significantly enhanced pancreatic acinar cell trypsin activity and aggravated AP severity in caerulein-induced, L-arginine-induced, pancreatic duct ligation, or combined bile and pancreatic duct ligation-induced murine AP models.…”

“… 16 However, growing research on the properties of bile acids as signaling molecules in recent years has led to a new understanding of the pathophysiological mechanisms underlying AP. 17 , 18 , 19 Clinical study has demonstrated that a transient increase in serum bile acids occurs within 24 h in the acute stage of AP. 20 Furthermore, the level of serum total bile acids was significantly higher in patients with AP of biliary etiology compared with those of alcohol and other etiologies, These findings suggest that bile acids can help in the early diagnosis of AP.…”

The role of gut microbiota in acute pancreatitis: new perspectives in pathogenesis and therapeutic approaches

“…Tran et al elucidated BAs could exacerbate L-arginine or pancreatic duct ligation induced AP, while protect against caerulein or biliopancreatic duct ligation induced pancreatic injury. [48] Recent studies showed gut flora and their enzymes could convert lithocholic acid into 3-oxolithocholic acid and isolithocholic acid, which block Th17 cell differentiation via inhibiting RORγt. [51] The role of liver-BAs-microbiota axis in improving insulin sensitivity and immunological balance during AP requires further exploration.…”

The Interaction of Microbiome and Pancreas in Acute Pancreatitis

“…Gut microbiota is involved in bile acid metabolism, and lifestyle affects human bile acid metabolism by regulating microbial genetics [27]. The gut microorganisms modulate bile acid synthesis and metabolism, inhibit the antiinflammatory effects of the NF-κB pathway [28], and block Th17 cell differentiation by inhibiting RORγt [29]. However, the role of intestinal flora and bile acid metabolism in AP requires further exploration [30].…”