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), irinotecan (CPT-11), oxaliplatin (L-OHP) and calcium folinate (CF) are the widely used chemotherapy drugs to treat colorectal cancer. However, the use of chemotherapy is often accompanied by intestinal inflammation and gut microbiota disorder. Moreover, 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. In this project, 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 (IFN-{gamma}, TNF-, IL-1{beta}, and IL-6) 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 (PICRUSt) analysis showed that the microbiota disorder pattern induced by 5-FU, CPT-11 and L-OHP was related to the NOD like signaling pathway. Therefore, we detected the protein expression of the NODs/RIP2/NF-{kappa}B signaling pathway and found that L-OHP activated that pathway highest. Furthermore, by RDA/CCA analysis, we found that Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, Streptococcus and Candidatus Saccharimonas were highly correlated with the NODs/RIP2/NF-{kappa}B signaling pathway, and influenced by chemotherapy drugs. IMPORTANCEThe chemotherapy-induced intestinal injury limit drugs clinical use. Intestinal injury involves multiple signaling pathways and the disruption of microbiota. Our results suggest that the degree of intestinal injury caused by different drugs of the first-line colorectal chemotherapy regimen is related to the change pattern of microbiota. Moreover, the NODs/RIP2/NF-{kappa}B signaling pathway was activated in different degrees is also related to the change pattern of microbiota. We found L-OHP caused the most severe change of gut microbiota, and showed considerable overlap of the microbiota changes pattern with 5-FU and CPT-11. Here, we have established a network of different chemotherapy drugs, gut microbiota and NODs/RIP2/NF-{kappa}B signaling pathway, which may provide a new basis for further elucidating the mechanism and clinical treatment of intestinal injury caused by chemotherapy.