Yi-Qi-Tong-Fu Decoction ameliorates acute sepsis induced intestinal failure by inhibiting epithelial apoptosis via IL-17 mediated PI3K/AKT signaling pathway: In silico analysis and experimental verification.

Sepsis is a life-threatening multi-organ involved diseases due to malfunctional immune response to pathogenic infections. Gut is usually deemed as a motor driver of sepsis. Yi-Qi-Tong-Fu Decoction (YQTFD) is specialized in treating gastrointestinal dysfunction. This study intends to illuminate the therapeutic mechanism of YQTFD by which IL-17 mediated PI3K/AKT signaling pathway regulates sepsis induced intestinal failure via epithelial apoptosis. The potential target signaling pathway was screened with network pharmacology and in silico analysis. The effects of YQTFD at low, medium and high doses (i.e. 5.18, 10.36 and 20.72 g/kg) on murine survival, intestinal pathological change, the gene and protein expressions related to tight junction, inflammation, apoptosis, and the activity of IL-17 mediated PI3K/AKT signaling pathway were assessed in a cecal ligation and puncture (CLP) induced sepsis model. The therapeutic effects of YQTFD drug-containing serum (YQTFD-DS) were also monitored in primary intestinal epithelial and Caco2 cells In silico analysis showed that IL-17 mediated PI3K/AKT signaling pathway might be a potential hub. In CLP mice, YQTFD could significantly extend life span, improve intestinal integrity, and reduce intestinal pathology, inflammation and apoptosis. In Caco2 cells, YQTFD-DS protected against LPS, CM and rIL-17 A induced cellular injuries and apoptosis in a dose-dependent manner. Silenced IL-17RA and PI3K remarkably blocked the therapeutic effect of YQTFD-DS via reactivating IL-17 mediated PI3K/AKT signaling pathway and apoptosis. Z-VAD-FMK also significantly negated the amelioration of YQTFD-DS against apoptosis. YQTFD has satisfactory therapy against sepsis induced intestinal injury via IL-17 mediated PI3K/AKT signaling pathway mediated epithelial apoptosis.