Epigallocatechin Gallate Alleviates Cisplatin Induced Intestinal Injury in Rats via Inhibiting NRF2/Keap1 Signaling Pathway and Regulating Gut Microbiota and Metabolites

Abstract

Cisplatin (CIS) is a broad-spectrum anticancer drug widely used in the clinic; however, one of its side effects is that it can cause intestinal damage such as loss of appetite, vomiting, and diarrhea in patients. Epigallocatechin gallate (EGCG) is one of the main active substances in green tea, which has the effects of antitumor multiple drug resistance, antioxidation, and antiinflammatory properties. The aim of this study was to explore the protective effect of EGCG on CIS-induced intestinal injury in rats. First, physiological indices and HE staining indicated that compared with the control group, the physiological state of rats in the CIS group was worse, and the intestinal tissue was damaged, especially the ileum. In contrast, pretreatment with EGCG (20, 40, and 80 mg/kg) effectively alleviated the intestinal damage induced by CIS, with the 40 mg/kg dose demonstrating the most substantial protective effect. Additionally, 40 mg/kg EGCG pretreatment mitigated CIS-induced morphological and ultrastructural damage to intestinal tissues, reduced bacterial translocation, and preserved the integrity of the intestinal barrier. This treatment also altered the abundance of 19 bacterial species, including Lactobacillus and Shigella, and influenced amino acid metabolism and 15 metabolic pathways, including vitamin B6 metabolism by 16S RNA and metabolome sequencing. Furthermore, the expression of proteins associated with autophagy and the NRF2/Keap1 signaling pathway was inhibited. Lastly, ML385 (NRF2 signaling pathway inhibitor) reversed the protective effects of EGCG. Taken together, our findings indicate that EGCG ameliorates CIS induced hepatoenteric toxicity in rats by regulating the intestinal flora and targeting the Nrf2/Keap1 signal axis.