Glycoside hydrolase-mediated utilization of Poria cocos polysaccharide enriches Lactobacillus gasseri and activates the AhR–IL-22 axis to attenuate DSS-induced colitis

Polysaccharides derived from edible fungi can alleviate ulcerative colitis (UC) by enriching beneficial probiotics. However, the mechanisms underlying their interaction with probiotics remain unclear. Here, The current study investigated how PCP enriches L. gasseri and the effects of L. gasseri on dextran sulfate sodium (DSS)-induced UC. Genomic analyses predicted multiple polysaccharide utilization loci in L. gasseri , and growth kinetics together with gene expression assays confirmed that PCP promoted L. gasseri growth and upregulated glycoside hydrolases (GH1 and GH3). In UC induced mice, L. gasseri alleviated weight loss, colon shortening, and Disease activity index score, increased goblet cells, and decreased pro-inflammatory cytokines. In addition, targeted metabolomics revealed that L. gasseri intervention was associated with the restoration of indole-3-lactic acid (ILA) and indole-3-propionic acid (IPA) levels in the tryptophan-indole metabolic pathway. RT-qPCR, Western blot, and immunofluorescence analyses showed that L. gasseri intervention induced the upregulation of AHR expression and the downstream genes CYP1A1 and IL-22. Treatment with the AHR antagonist CH223191 further confirmed that the anti-inflammatory and barrier-protective effects were dependent on the AHR pathway. Notably, It was further verified through ABX depletion experiments that PCP exerts its indirect therapeutic effect via L. gasseri . Consequently, this study provided new insights into the interaction between PCP and probiotics the mechanism underlying the protective role of L. gasseri in the intestinal barrier, and proposes promising preliminary combination strategy for the treatment and prevention of UC. Poria cocos polysaccharide is utilized by L. gasseri , activating the AhR–IL-22 axis to enhance intestinal barrier function, modulates the gut microbiota, and alleviate ulcerative colitis. • The medicinal and edible fungal polysaccharide PCP ameliorates ulcerative colitis (UC) and enriches the probiotic L. gasseri . • L. gasseri induces tryptophan metabolism to stimulate the production of microbial indole derivatives. • L. gasseri modulates gut immunity and restores the intestinal barrier via the AHR/IL 22 pathway. • Multi-evidence (genomics, docking, growth, transcription) shows L. gasseri recognizes and utilizes PCP