The Akkermansia muciniphila-tryptophan metabolism-aromatic hydrocarbon receptor axis mediates the protective effect of Schisandra chinensis pectin polysaccharide against colitis.

Current therapies for ulcerative colitis (UC) remain inadequate, necessitating novel treatment strategies. This study isolated SCPII-1, a homogeneous pectin polysaccharide (Mw: 278.153 kDa, DM: 57.21 %) from Schisandra chinensis, primarily composed of →4)-α-D-GalpA-(1 → units. In dextran sulfate sodium (DSS)-induced colitis mice, SCPII-1 alleviated symptoms, repaired mucosal ultrastructure (microvilli, mitochondria), and enhanced barrier integrity. Mechanistically, SCPII-1 ameliorated gut dysbiosis in UC mice, notably through the selective enrichment of the beneficial bacterium Akkermansia muciniphila (AKK). Interestingly, SCPII-1 not only promoted the proliferation of AKK but also modulated its tryptophan metabolism, particularly enhancing the production of the tryptophan-derived metabolite indole-3-ethanol (I3E). The beneficial role of SCPII-1-induced microbiota in UC was validated using pseudo-germ-free mice and fecal microbiota transplantation experiments. Moreover, I3E was identified as a key microbiota-derived active metabolite regulated by SCPII-1, and exogenous supplementation of I3E further confirmed its therapeutic efficacy in UC. Importantly, I3E activated the aryl hydrocarbon receptor (AhR), upregulated IL-22 expression, and promoted mucosal repair and immune homeostasis, thereby confirming the protective role of the SCPII-1-AKK-tryptophan metabolism axis in colitis. These findings highlight SCPII-1 as a promising prebiotic agent for UC treatment by modulating AKK-dependent tryptophan metabolism and activating the AhR/IL-22 signaling pathway, offering a novel microbiota-based therapeutic strategy.