Study on the correlation between gut microbiota and metabolite, brevifolincarboxylic acid, and liver injury caused by third-generation EGFR-TKIs in lung adenocarcinoma.

Abstract

e20552 Background: For patients with non-small cell lung cancer (NSCLC) who are treated with third-generation EGFR-TKIs, drug-induced liver injury (DILI) is a common adverse reaction that affects the therapeutic outcome. The gut microbiota and metabolites may participate in the occurrence of DILI through the gut-liver axis. Methods: From the clinical samples, 41 patients with lung adenocarcinoma who received first-line treatment with third-generation EGFR-TKI from April 2021 to April 2023 were enrolled in this study. According to the presence or absence of DILI, they were divided into DILI group (group D, n = 18) and N group (n = 23). Fecal metagenomic sequencing and untargeted metabolomics analysis were used to compare the differences in gut microbiota composition and metabolites between the fecal samples of patients with DILI at the time of DILI (Doccur group) and at baseline (Dbase group). The CCK-8 assay, LDH kit, colony formation experiment and flow cytometry were used to investigate whether BA could enhance the inhibitory effect of osimertinib on hepatocytes. Establish an mouse model of oxaliplatin-induced liver injury, and investigate the regulatory effects of BA on liver tissue pathology, serum liver enzymes (ALT/AST/LDH), and inflammatory factors.The TLR4/MyD88/NF- κB signaling pathway was analyzed through transcriptome sequencing, Western blot and ELISA. Results: The diversity of the intestinal flora in DILI patients was significantly reduced, while the abundance of Bacteroides / Faecalibacterium species increased, and the abundance of Clostridium decreased; the level of metabolite Brevifolincarboxylic acid（BA） was significantly downregulated.BA pre-treatment can reverse the hepatocyte toxicity induced by osimertinib (inhibiting apoptosis, reducing LDH release, and improving proliferation ability). BA intragastric administration alleviates liver tissue inflammatory damage in mice, significantly reducing serum levels of ALT/AST/LDH as well as inflammatory factors (IL-6/IL-1β/TNF-α). BA may exert liver-protective effects by inhibiting the activation of the TLR4/MyD88/NF- κB signaling pathway. Conclusions: By regulating the TLR4/MyD88/NF- κB signaling pathway, BA alleviates liver damage induced by third-generation EGFR-TKIs, providing a new target for the prevention and treatment of DILI based on the intestinal-liver axis.