Shengjiang Xiexin Decoction Mitigates Irinotecan-Triggered Delayed-Onset Diarrhea by Modulating Short-Chain Fatty Acids and the TLR4-MyD88-JNK/ NF-κB Pathway.

INTRODUCTION

Delayed-onset diarrhea, a common adverse reaction to irinotecan, affects both the effectiveness of chemotherapy and the quality of life of cancer patients. This type of diarrhea has been effectively treated with Shengjiang Xiexin decoction (SXD), a staple in traditional Chinese medicine (TCM). This study sought to clarify the pharmacological mechanism by which SXD alleviates irinotecan-induced diarrhea.

METHODS

Irinotecan-triggered delayed-onset diarrhea was modeled in rats, and effectiveness was investigated by evaluating body weight, diarrhea score, and intestinal mucosal pathology. The research investigated tight junction protein expressions in intestinal epithelial cells (IECs), especially Zonula occludens-1 (ZO-1) and occludin, by immunofluorescence (IF) labeling. Furthermore, intestinal permeability was evaluated utilizing the fluorescence-labeled isothiocyanate (FITC) glucan technique. Intestinal short-chain fatty acids (SCFAs) were quantified by use of ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and colorimetric analysis was utilized to assess β-glucuronidase activity in the gut. Finally, the mRNA expressions of TLR4-Myd88-JNK/NF-κB and Muc2 in the gut were quantified by use of reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR).

RESULTS

SXD had considerable protective benefits in rats, alleviating body weight loss, decreasing diarrhea scores, and diminishing intestinal mucosal damage and permeability. The therapy increased the expression of ZO-1 and occludin proteins, therefore preserving the integrity of the intestinal mucosal barrier. Moreover, SXD significantly elevated SCFA levels in the gut while reducing β-glucuronidase activity. SXD reduced the mRNA levels of JNK, NF-κB, Myd88, and TLR4, while increasing those of Muc2 in rat jejunum tissues.

DISCUSSION: SXD ameliorates irinotecan-induced diarrhea via a multi-mechanism approach, including inhibition of bacterial β-glucuronidase, restoration of beneficial short-chain fatty acids, enhancement of intestinal barrier integrity, and suppression of the TLR4/MyD88/NF-κB inflammatory pathway.

CONCLUSION

This study provides a foundation for further investigation of SXD as a complementary strategy to improve the safety of irinotecan chemotherapy.