Gut Microbiota-driven Tryptophan Metabolism Towards the Indole Pathway Mediates Schisandra Chinensis Polysaccharide's Alleviation of Ulcerative Colitis and Comorbid Depression via Aryl Hydrocarbon Receptor.

Patients with ulcerative colitis (UC) exhibit heightened depression risk, linked to microbiota-gut-brain axis dysfunction. This study isolated a novel low-molecular-weight Schisandra chinensis polysaccharide (SCP) that ameliorated UC and comorbid depression by remodeling gut microbiota, redirecting tryptophan (Trp) metabolism toward the indole pathway, and activating aryl hydrocarbon receptor (AhR). Structurally, SCP features a →4)-α-D-Glcp backbone with O-6 branched chains. In dextran sulfate sodium-induced UC mice, SCP mitigated colonic inflammation, restored intestinal barrier integrity, and improved depression-like behaviors by repairing blood-brain barrier, reducing neuroinflammation, preserving hippocampal neurons, and modulating synaptic plasticity. Multi-omics revealed SCP enriched beneficial microbiota (e.g., Limosilactobacillus reuteri) and rebalanced Trp metabolism along the gut-brain axis. SCP suppressed the hyperactive kynurenine (Kyn) pathway (reduced Kyn/Trp ratio) while elevating indole-3-propionic acid (IPA) levels in colon, serum, and hippocampus. Functioning as a pivotal molecule, IPA exerted dual anti-inflammatory effects in both colon and hippocampus via AhR activation and NF-κB inhibition. Antibiotic depletion and fecal microbiota transplantation validated SCP's microbiota-dependent efficacy, while IPA supplementation recapitulated SCP's benefits. AhR inhibition abolished SCP's therapeutic actions, confirming AhR as the critical target. Collectively, these findings propose a novel therapeutic strategy for UC and associated depression, highlighting SCP's potential value in targeting the Trp metabolism-AhR axis.