Forsythiae Fructus attenuates DSS-induced colitis and associated neuroinflammation with modulation of AMPK/mTOR-related autophagy signaling.

Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl is a traditional herbal medicine widely used in East Asia for inflammatory disorders. Although Forsythiae Fructus exhibits anti-inflammatory activity in experimental colitis, its effects on colitis-associated brain inflammation and autophagy-related signaling remain unclear. This study investigated the protective effects of Forsythiae Fructus extract (FF) on intestinal and brain inflammatory responses in dextran sulfate sodium (DSS)-induced colitis mice and explored the involvement of AMPK/mTOR-related signaling. Mice received FF (100 mg/kg) or 5-aminosalicylic acid (ASA, 100 mg/kg) by oral gavage once daily for 15 days. DSS (5%, w/v) was administered in drinking water from day 7 to day 12, followed by a 3-day recovery period with normal drinking water (day 12-15). Disease severity, intestinal permeability, inflammatory mediators, and autophagy-related markers in the colon and brain were assessed using endoscopy, histology, ELISA, immunoblotting, immunofluorescence, and RT-qPCR. FF substantially alleviated DSS-induced colitis by attenuating body weight loss (-9.0% vs. -17.1% in DSS), reducing the disease activity index by approximately 40%, increasing colon length by 18%, and decreasing intestinal permeability by approximately 59%. FF restored epithelial barrier integrity by increasing Occludin, ZO-1, Muc2, and Tff3 expression. It also decreased IL-1β, IL-6, and TNF-α levels in the colon, serum, and brain, accompanied by reduced microglial activation and NF-κB signaling. FF increased AMPK phosphorylation and LC3B-II/LC3B-I ratios while reducing mTOR activation and SQSTM1 accumulation in both colon and brain tissues. FF effectively alleviated DSS-induced colitis, reducing disease activity by approximately 40% and restoring intestinal barrier function. These protective effects were accompanied by suppression of intestinal and brain inflammatory responses and modulation of AMPK/mTOR-related autophagy signaling. These findings provide experimental support for the traditional use of FF in inflammatory disorders and highlight its potential as a protective candidate for ulcerative colitis and its associated gut-brain inflammatory manifestations.