Poria cocos polysaccharides alleviate colitis via the tryptophan metabolism-AhR-redox axis

Poria cocos (Fuling), a classic edible and medicinal fungus with a 2000-year clinical application history in traditional Chinese medicine, is well-documented for its core efficacies of "invigorating the spleen and relieving diarrhea", which is highly consistent with the core clinical manifestations of infectious colitis including persistent diarrhea, intestinal barrier impairment and mucosal inflammation. Poria cocos polysaccharides (PCP) are recognized as the primary bioactive component of Poria cocos, with proven anti-inflammatory and immunomodulatory activities. However, whether PCP exerts its anti-colitis effect via regulating the tryptophan (Trp) metabolism-aryl hydrocarbon receptor (AhR) signaling axis remains largely uncharacterized.

This study aimed to investigate the therapeutic effect of PCP on Salmonella-induced infectious colitis in mice, and systematically elucidate its underlying molecular mechanism focusing on the Trp metabolism-AhR-redox signaling axis.

A Salmonella typhimurium-induced infectious colitis mouse model was established to evaluate the protective effect of PCP (100, 200, 400 mg/kg) via oral administration. Targeted metabolomics was performed to profile the changes of intestinal Trp metabolites in colitis mice. Histopathological examination, immunohistochemistry, immunofluorescence, western blot, and real-time quantitative PCR were conducted to assess intestinal barrier integrity, intestinal redox status, and the activation of relevant signaling pathways. Molecular docking simulation was used to verify the direct interaction between the key differential metabolite and its target proteins.

PCP administration significantly alleviated the clinical symptoms of infectious colitis, restored colon length and organ indices (P < 0.05), and ameliorated colonic pathological damage in a dose-dependent manner. PCP markedly reinforced intestinal epithelial barrier integrity via upregulating the protein expression of tight junction proteins including ZO-1, Occludin and Claudin (P < 0.01). Targeted metabolomics analysis revealed that PCP intervention effectively remodeled the disordered intestinal Trp metabolic profile, especially significantly enriched the endogenous AhR ligand indole-3-lactic acid (I3LA) by 5.5-fold compared with the model group (P < 0.05). Mechanistically, PCP promoted the nuclear translocation of AhR, normalized the aberrant NRF2/HO-1 signaling pathway to restore intestinal redox homeostasis, and subsequently suppressed the hyperactivation of JAK/STAT3 and NF-κB inflammatory cascades, with the mRNA levels of core pro-inflammatory cytokines IL-6 and TNF-α reduced by more than 70% (P < 0.01).

Collectively, these findings demonstrate that PCP ameliorates Salmonella-induced infectious colitis via remodeling the intestinal Trp metabolic microenvironment to enrich I3LA, which acts as a molecular switch to activate the AhR-redox axis and further suppress mucosal inflammatory responses. This study provides modern scientific evidence for the traditional "invigorating the spleen and relieving diarrhea" clinical application of Poria cocos, and supports the potential of PCP as a safe and effective prebiotic agent for the prevention and treatment of intestinal inflammatory diseases.