Abstract
Chemotherapy-induced intestinal mucositis (CIM) is a significant dose-limiting adverse effect of cancer treatment. Huangqi Baihe Granules (HQBHG) derived from Dunhuang’s ancient medical texts could alleviate radiation brain injury and hypobaric hypoxia-induced acute lung injury. Here, the protective effect and mechanism of HQBHG against irinotecan (CPT-11)-induced intestinal mucositis were detected by using Drosophila melanogaster and mouse models. Oral administration of HQBHG could significantly ameliorate body injury caused by CPT-11, including increased survival rate, rescued locomotion, altered metabolic capacity, restoration of ovarian morphology in flies, and also alleviated body weight loss and diarrhea in mice. Meanwhile, HQBHG supplementation resumed intestinal length and gastrointestinal acid-based homeostasis, reduced epithelial cell death in CPT-11 treated flies. In CPT-11 treated mice, HQBHG increased the gut length, recovered the architecture of the mucosa, and increased the expressions of tight junction proteins (ZO-1 and occludin ). Mechanism study showed that HQBHG remarkably down-regulated the expression levels of NF-κB signaling, the levels of cytokines IL-1β and TNF-α, and intestinal ROS accumulation; whereas it significantly up-regulated the levels of IL-10, and the expression of the Keap1/Nrf2 signaling in the guts. In addition, integrated analysis of 16S rDNA gene sequencing and untargeted metabolomics revealed that HQBHG reversed CPT-11-induced disordered amino acid metabolism of phenylalanine, tyrosine, tryptophan and glycine, which was closely related to the diversity and abundance of gut microbiota such as Escherichia-Shigella and Clostridium_sensu_stricto. Therefore, HQBHG has the potential to be an effective agent for the treatment of CIM by inhibiting the NF-κB pathway, activating the Nrf2/Keap1 pathway and regulating the amino acid metabolism balance in the gut.
