The polysaccharide from Usnea longissima ach. ameliorates DSS-induced ulcerative colitis by restoring gut microbiota homeostasis and inhibiting the NF-κB/PI3K-Akt signaling pathways.

Usnea longissima Ach. has long been used in traditional medicine for inflammatory and infectious disorders, but its therapeutic potential and immunological mechanism in ulcerative colitis remain unclear. In this study, we investigated the protective effects of Usnea longissima Ach. Polysaccharide (USLP) against dextran sulfate sodium-induced colitis in mice and explored its microbiota-associated mucosal immune mechanism. USLP markedly alleviated colitis symptoms, as shown by reduced body weight loss and disease activity index, preservation of colon length, and improvement of histopathological injury. USLP also restored epithelial barrier integrity by increasing the expression of occludin, claudin-1 and ZO-1. Importantly, USLP rebalanced systemic cytokine levels by suppressing DSS-induced TNF-α and IL-1β production while enhancing the regulatory cytokine IL-10, suggesting restoration of intestinal immune homeostasis. 16S rRNA sequencing showed that USLP remodeled DSS-induced gut microbiota dysbiosis, characterized by enrichment of Lactobacillus-associated beneficial taxa and reduction of DSS-expanded pathobiont-associated taxa such as Bacteroides. These microbial changes were closely correlated with inflammatory cytokines and barrier-related markers. Integrated transcriptomic analysis revealed that USLP reversed immune-inflammatory transcriptional alterations in the colonic mucosa, with PI3K-Akt signaling identified as a key pathway. Western blot further confirmed that USLP inhibited DSS-induced phosphorylation of PI3K and Akt. Collectively, these findings indicate that USLP protects against DSS-induced colitis, at least partly, by restoring microbiota-barrier-immune homeostasis and suppressing PI3K-Akt-associated mucosal inflammatory signaling, supporting its potential as an immunomodulatory candidate for UC intervention.