Gut Microbiota-driven Tryptophan Metabolism Towards the Indole Pathway Mediates <i>Schisandra Chinensis</i> 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 <i>Schisandra chinensis</i> 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-Glc<i>p</i> backbone with <i>O</i>-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., <i>Limosilactobacillus reuteri</i>) 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.