Indirubin mediates adverse intestinal reactions in guinea pigs by downregulating the expression of AchE through AhR

Abstract

1. Indirubin is the main component of the traditional Chinese medicine Indigo naturalis (IN), a potent agonist of aryl hydrocarbon receptors (AhRs). In China, IN is used to treat psoriasis and ulcerative colitis, and indirubin is used for the treatment of chronic myelogenous leukaemia. However, IN and indirubin have adverse reactions, such as abdominal pain, diarrhoea, and intussusception, and their specific mechanism is unclear.

2. The purpose of our research was to determine the specific mechanism underlying the adverse effects of IN and indirubin. By tracking the modifications in guinea pigs after the intragastric administration of indirubin for 28 days.

3. The results demonstrate that indirubin could accelerate bowel movements and decrease intestinal acetylcholinesterase (AchE) expression. Experiments with NCM460 cells revealed that indirubin significantly reduced the expression of AchE, and the AchE levels were increased after the silencing of AhR and re-exposure to indirubin.

4. This study showed that the inhibition of AchE expression by indirubin plays a key role in the occurrence of adverse reactions to indirubin and that the underlying mechanism is related to AhR-mediated AchE downregulation.

Keywords:

• Indirubin
• intestinal adverse reactions
• aromatic hydrocarbon receptor
• acetylcholinesterase
• species difference

Acknowledgment

We would like to express our gratitude to Sun Li Xin, who guided us throughout this project. I would also like to thank Chenghan Chu for helping to complete this project. As well as Li Xiao, Tao Wang, Xinzhi Wang, Xin Huang, and Zhenzhou Jiang for their contribution to the experiment guidance and revising the final manuscript. Finally, great thanks to the National Natural Science Foundation of China, which funds this project.

Author contributions

Xu Xiaoting performed the experiments, collected data, analysed the data and wrote the manuscript. Reham Elfadil worked equally with xu xiaoting as first co-author. Chenghan Chu performed parts of the experiments and collected the data. Li Xiao, Tao Wang, Xinzhi Wang, Xin Huang, and Zhenzhou Jiang contributed to the guidance of experiments and contributed to the final manuscript. Lixin Sun designed the study and contributed to the final manuscript. All the authors reviewed the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China under grant numbers (82074115, 81873084 and 82174072).