Sophoraflavanone G alleviates ulcerative colitis in mice by reshaping the gut microbiome and restoring the Th17/Treg balance through the PI3K/AKT/NF-κB signaling pathway.

Ulcerative colitis (UC) is characterized by diarrhea, bloody stool and a feeling of incomplete defecation. Sophoraflavanone G (SFG) is one of the main chemical components of Sophora flavescens Ait and possesses various pharmacological activities. This study aims to investigate the therapeutic efficacy of naturally derived SFG in alleviating dextran sulfate sodium (DSS)-induced UC and the underlying mechanisms. A mouse model of DSS-induced UC was created and treated with SFG, antibiotics (ABX) cocktail, or the AKT agonist SC79. Clinical symptoms and signs of UC were assessed. Expression levels of inflammatory factors, tight junction proteins, and mucin-2 (MUC-2) in colon tissues were detected. The underlying mechanism by which SFG relieved UC in mice was elucidated by RNA sequencing (RNA-Seq), network pharmacology, molecular docking and molecular dynamics simulation, and validated in mouse colon tissues. Furthermore, the effects of SFG in remodeling the gut microbiome and restoring the Th17/Treg balance were explored. The results showed that SFG significantly decreased the Disease Activity Index (DAI) score, alleviated bloody diarrhea, splenomegaly, and colon shortening in UC mice; it effectively suppressed the serum and colonic levels of inflammatory factors, and significantly upregulated the expression of tight junction proteins and MUC-2 in colon tissues. Furthermore, molecular studies demonstrated that SFG may bind to p110α to inhibit the PI3K/AKT/NF-κB signaling pathway and further regulate the Th17/Treg balance. Meanwhile, SFG restores the gut microbiome. In conclusion, this study confirms that SFG has a significant therapeutic effect on DSS-induced UC. The underlying mechanism may be partially attributed to the binding of SFG to p110α, which inhibits the PI3K/AKT/NF-κB pathway and further regulates the Th17/Treg balance; and restores the gut microbiome to alleviate UC. This research offers a novel natural candidate foundation for the clinical treatment of UC.