2. Academic Validation
  3. Treatment with S-adenosylmethionine ameliorates irinotecan-induced intestinal barrier dysfunction and intestinal microbial disorder in mice

Treatment with S-adenosylmethionine ameliorates irinotecan-induced intestinal barrier dysfunction and intestinal microbial disorder in mice

  • Biochem Pharmacol. 2023 Aug 25;115752. doi: 10.1016/j.bcp.2023.115752.
Lin Xiao 1,  Weidong Dou 1,  Yajie Wang 1,  Huan Deng 1,  Hao Xu 2,  YiSheng Pan 3
Affiliations

Affiliations

  • 1 Department of General Surgery, Peking University First Hospital, No.8 Xishiku Street, Beijing 100034, China.
  • 2 Department of General Surgery, Peking University First Hospital, No.8 Xishiku Street, Beijing 100034, China. Electronic address: [email protected].
  • 3 Department of General Surgery, Peking University First Hospital, No.8 Xishiku Street, Beijing 100034, China. Electronic address: [email protected].
PMID: 37634598 DOI: 10.1016/j.bcp.2023.115752
Abstract

This study aimed to investigate the protective effects of S-adenosylmethionine (SAM) on irinotecan-induced intestinal barrier dysfunction and microbial ecological dysregulation in both mice and human colon cell line Caco-2, which is widely used for studying intestinal epithelial barrier function. Specifically, this study utilized Caco-2 monolayers incubated with 7-ethyl-10-hydroxycamptothecin (SN-38) as well as an irinotecan-induced diarrhea model in mice. Our study found that SAM pretreatment significantly reduced body weight loss and diarrhea induced by irinotecan in mice. Furthermore, SAM inhibited the increase of intestinal permeability in irinotecan-treated mice and ameliorated the decrease of Zonula occludens-1(ZO-1), Occludin, and Claudin-1 expression. Additionally, irinotecan treatment increased the relative abundance of Proteobacteria compared to the control group, an effect that was reversed by SAM administration. In Caco-2 monolayers, SAM reduced the expression of Reactive Oxygen Species (ROS) and ameliorated the decrease in transepithelial electrical resistance (TER) and increase in fluorescein isothiocyanate-dextran 4000 Da (FD-4) flux caused by SN-38. Moreover, SAM attenuated changes in the localization and distribution of ZO-1and Occludin in Caco-2 monolayers induced by SN-38 and protected barrier function by inhibiting activation of the p38 MAPK/p65 NF-κB/MLCK/MLC signaling pathway. These findings provide preliminary evidence for the potential use of SAM in treating diarrhea caused by irinotecan.

Keywords

Chemotherapy; Gut microbiota; Irinotecan; SAM; Tight junction proteins; p38 MAPK/p65 NF-κB/MLCK/MLC signaling pathway.

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