Chemotherapy drugs induce different gut microbiota disorder pattern and NODs/RIP2/NF-κB signaling pathway activation that lead to different degrees of intestinal injury

Abstract

5-Fluorouracil (5-FU), oxaliplatin (L-OHP) ,etc .used chemotherapy drugs to treat colorectal cancer. chemotherapy is often accompanied by intestinal inflammation and gut microbiota disorder. The change of gut microbiota may lead to destruction of the intestinal barrier, which contributes to the severity of intestinal injury. There was no detailed comparison of intestinal injury and gut microbiota disorder among 5-FU, CPT-11, L-OHP and CF, which is not benefit for the development of targeted detoxification therapy after chemotherapy. A model of chemotherapy-induced intestinal injury in tumor-bearing mice was established by intraperitoneal injection of chemotherapy drugs at a clinically equivalent dose. 16S rDNA sequencing was used to detect gut microbiota. We found that 5-FU, CPT-11 and L-OHP caused intestinal injury, inflammatory cytokine secretion, and gut microbiota disorder. Importantly, we established a complex but clear network between the gut microbiota change pattern and intestinal damage degree induced by different chemotherapy drugs. L-OHP caused the most severe damage in intestine and disorder of gut microbiota, and showed considerable overlap of the microbiota change pattern with 5-FU and CPT-11. The phylogenetic investigation of communities by reconstruction of unobserved states, V1.0 analysis showed that the microbiota disorder pattern induced by 5-FU, CPT-11 and L-OHP was related to the NOD like signaling pathway. we detected the protein expression of the NODs/RIP2/NF-κB signaling pathway and found that L-OHP activated that pathway highest. By RDA/CCA analysis, Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, etc. correlated with the NODs/RIP2/NF-κB signaling pathway, and influenced by chemotherapy drugs.