Conclusion
Conjugated bile acids significantly inhibit NLRP3 inflammasome activation by activating TGR5 pathway, thereby alleviating pancreatic immunopathology. The results provide new insights into the variability of clinical outcomes and paves the way for developing more effective therapeutic interventions for AP.
Methods
To test our hypothesis, we used BA-CoA: amino acid N-acyltransferase knockout (Baat-/-) mice and established SAP mouse models using caerulein- and sodium taurocholate- induced. We utilized a range of methods, including pathology sections, qRT-PCR, immunofluorescence, Western blotting, and ELISA, to identify the mechanisms of regulation.
Results
BA-CoA: Amino acid N-acyltransferase knockout (Baat-/-) mice significantly exacerbated pancreatitis by increasing pancreatic and systemic inflammatory responses and pancreatic damage in SAP mouse models. Moreover, the serum TCDCA levels in Baat-/- mice were lower than those in wild-type (WT) mice with or without SAP, and GCDCA and TCDCA showed stronger anti-inflammatory effects than chenodeoxycholic acid (CDCA) in vitro. TCDCA treatment alleviated SAP in a Takeda G protein-coupled receptor 5 and NOD-like receptor family, pyrin domain containing 3-dependent manner in vivo. Reinforcing our conclusions from the mouse study, clinical SAP patients exhibited decreased serum content of conjugated BAs, especially GCDCA, which was inversely correlated with the severity of systemic inflammatory responses.