Paeonia lactiflora pall. Polysaccharide attenuates inflammation and improves intestinal barrier function in ulcerative colitis mice by modulating intestinal flora and inhibiting S100A8/A9/NF-κB signaling.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) with substantial clinical burden and limited treatment options. PLPN-2, an α-glucan extracted from P. lactiflora, has shown anti-inflammatory activity in cellular and animal models, but its therapeutic mechanisms in UC remain unclear. Here, mice were exposed to 3% DSS and treated with PLPN-2 (40, 80, or 160 mg/kg/day) to evaluate its anti-colitic effects. PLPN-2 significantly alleviated colitis, with the high-dose group showing a 55.2% reduction in the day 8 disease activity index (DAI) versus the DSS group. It also alleviated inflammatory infiltration, reflected by a 47.5% decrease in colonic MPO content, improved intestinal barrier integrity and reshaped the gut microbiota based on 16S rRNA sequencing, with the Chao 1 index reaching nearly threefold that of DSS-treated mice. Cytokine microarray revealed significant downregulation of IL-17 pathway activity, while TMT-based quantitative proteomics identified S100A8/A9 as a key IL-17-associated inflammatory mediator targeted by PLPN-2. In vitro, PLPN-2 suppressed S100A8/A9 secretion from activated THP-1 cells and attenuated downstream NF-κB activation, whereas S100A8/A9 overexpression reversed these protective effects. In conclusion, PLPN-2 ameliorates DSS-induced colitis by modulating dysbiosis and blocking S100A8/A9-driven NF-κB activation, supporting its protential as a preclinical candidate for UC therapy.