Forsythiaside A (FA), the primary compound found in Forsythia suspensa (Thunb.) Vahl, has demonstrated various pharmacological effects, but its impact on ulcerative colitis (UC) is underexplored. Our study examined the distribution of FA in different parts of the gastrointestinal tracts and its therapeutic effects on UC, along with the underlying mechanisms. The levels of FA in gastrointestinal tracts and plasma were analyzed by high-performance liquid chromatography
mice were given dextran sulfate sodium in drinking water to develop the UC model. The UC mice were treated with FA (15, 30, and 60 mg/kg) for 10 days. FA showed relatively high concentration retention in the colon within 4 h. The treatment of FA improved body weight loss, diarrhea, rectal bleeding, colon shortening, and histological damage in UC mice. It also increased the expression of the tight junction protein and decreased inflammatory cytokines in the colon. The microbiota analysis using 16S rRNA sequencing revealed that FA could alleviate gut dysbiosis in colitis mice. Of importance, we found FA resulted in a reduction of neutrophil extracellular traps formation (NETosis) and inhibited peptidyl arginine deiminase 4 (PAD4) in colon tissue of colitis mice. In cultured neutrophils, FA pretreatment led to a suppression of PAD4 expression and NETosis induced by PMA. These findings suggest that FA can be retained in the colon and may alleviate UC by inhibiting NETs formation, indicating its potential for preventing or treating UC.