Platycodin D ameliorates antibiotic-associated diarrhea by modulating the PI3K/AKT/NF-κB pathway and regulating gut microbiota and metabolism.

Antibiotic-associated diarrhea (AAD) is a clinical condition characterized by diarrhea, vomiting, and fever, typically resulting from inappropriate or excessive use of antibiotics. Platycodin D (PD), a major bioactive compound of Platycodon grandiflorum, exhibits antioxidant, anti-inflammatory, and antitumor activities. However, whether PD can mitigate AAD remains unclear, and its effects on gut microbiota and metabolites have not been extensively studied. To address this knowledge gap, we established an AAD mouse model to investigate the effects and underlying mechanisms of PD through assessments of clinical indicators, biochemical parameters, histopathology, gut microbiota, and metabolomics. Our results demonstrated that PD supplementation significantly alleviated AAD symptoms in mice and improved intestinal barrier function, colonic inflammation, and oxidative stress. Western blot analysis revealed that PD mitigated AAD by modulating the PI3K/AKT/NF-κB and Nrf2/Keap1 signaling pathways. Furthermore, gut microbiota and metabolomic analyses indicated that PD improved the intestinal microbial composition, increased the Firmicutes-to-Bacteroidetes (F/B) ratio, and modulated several metabolic pathways, including D-amino acid metabolism, cysteine and methionine metabolism, and primary bile acid biosynthesis. In conclusion, these findings suggest that PD alleviates AAD through modulation of the PI3K/AKT/NF-κB and Nrf2/Keap1 pathways, as well as gut microbiota and metabolites, providing novel insights into the prevention and treatment of AAD.