Niu Huang mitigates dextran sulfate sodium-induced colitis by modulating farnesoid X receptor activation and the complement 3/NLRP3 signaling pathway

Abstract

BACKGROUND

Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which effective therapies are lacking. Niu Huang (NH) is a traditional Chinese medicine used for inflammatory disorders. However, its protective effect on UC and its underlying mechanisms are unknown.

AIM

To uncover the mechanisms underlying the anti-colitis effects of the NH.

METHODS

Network pharmacology was applied to predict the active ingredients and targets of NH. Experimental validation was conducted in a dextran sulfate sodium-induced murine colitis model. The therapeutic efficacy was assessed using symptoms, histopathology, quantitative polymerase chain reaction, western blotting, immunohistochemistry and enzyme linked immunosorbent assay, while the underlying mechanism was investigated through integrated transcriptomic and proteomic analyses. In addition, the critical role of farnesoid X receptor (FXR) in mediating the effects of NH was validated using the FXR inhibitor guggulsterone and Fxr^-/- mouse models.

RESULTS

Network pharmacology revealed that the bioactive component of NH is bile acid. Our animal experiments demonstrated that NH treatment significantly alleviated colitis symptoms and pathological damage. NH preserved intestinal mucosal integrity by upregulating occludin, claudin3, E-cadherin and leucine rich repeat containing G protein-coupled receptor 5 expression. Transcriptomic and proteomic analyses revealed that bile secretion, the nuclear factor kappa B signaling pathway and the complement and coagulation cascade pathway are key targets of NH. Western blotting confirmed that NH increased FXR levels and reduced P65, complement component 3 (C3) and NOD-like receptor family pyrin domain containing 3 (NLRP3) expression. Furthermore, experiments using Fxr^-/- mice and the FXR antagonist revealed that FXR is a pivotal target through which NH attenuates UC. Mechanistic analysis revealed that the effects of NH on UC are mediated by the modulation of targets involved in the activation of FXR and the subsequent inhibition of C3/NLRP3 activation.

CONCLUSION

This study demonstrates the therapeutic effects of NH on UC. Mechanistically, NH acts by activating FXR, which subsequently inhibits the nuclear factor kappa B pathway to reduce C3 accumulation and suppress excessive NLRP3 inflammasome activation in colon tissue.

Keywords: Niu Huang; Ulcerative colitis; Network pharmacology; Farnesoid X receptor; Complement component 3/NOD-like receptor family pyrin domain containing 3 signaling pathway; Inflammation

Core Tip: This study demonstrates that Niu Huang effectively alleviates ulcerative colitis. By identifying its active components and employing transcriptomic and proteomic sequencing to predict mechanisms, this study reveals that this drug exerts anti-colitis effects by activating the farnesoid X receptor (FXR), which subsequently inhibits nuclear factor kappa B transcription. This inhibition reduces the accumulation of complement component 3 and suppresses excessive activation of the NOD-like receptor family pyrin domain containing 3 inflammasome in colon tissue, alleviating intestinal inflammation. The critical role of FXR was conclusively validated using both FXR antagonist guggulsterone and Fxr-knockout mouse models.