Rhein alleviates acute pancreatitis by inhibiting TMAO-mediated inflammatory signaling pathways and reducing acinar cell injury.

INTRODUCTION

Acute pancreatitis (AP) represents a significant global health challenge. Despite recent advances in medical treatment, the development of novel therapeutic strategies remains crucial.

OBJECTIVES

Rhein, a natural compound of the Chinese herb Rheum, shows promise in the treatment of AP. However, the exact mechanism underlying its therapeutic effect is still not fully understood.

METHODS

To investigate the association between the rhein-related gut microbiota and AP, we conducted antibiotic-mediated microbiota depletion experiments, fecal microbiota transplantation (FMT), and in vitro bacterial culture experiments. Concurrently, we performed 16S rRNA gene sequencing, metagenomic sequencing, and liquid chromatography‒mass spectrometry (LC‒MS) analyses on mouse fecal samples to characterize alterations in the microbiota and metabolome. Transcriptomic studies were also performed to elucidate the mechanisms underlying acinar cell inflammation.

RESULTS

Rhein alleviated AP by modulating the gut microbiota, as demonstrated by changes in the gut microbiota composition and improvements in AP after FMT in rhein-treated mice compared with those in cerulein-induced AP mice. Specifically, rhein is concentrated mainly in the stomach and intestines, where it exerts anti-inflammatory effects on acinar cells by antagonizing the TLR4/NF-κB/NLRP3 signaling pathway activated by trimethylamine-N-oxide (TMAO). This mechanism is associated with lipid peroxidation and necrosis mediated by oxidative stress. Clinically, disease severity in patients with AP is positively correlated with serum TMAO concentration.

CONCLUSION

Rhein alleviates AP by modulating the intestinal microbiota to reduce TMAO production, thereby suppressing TMAO-induced activation of the TLR4/NF-κB/NLRP3 signaling pathway and inhibiting acinar cell inflammation.