Microbiome–Metabolomics Analysis Reveals the Mechanism of Holothuria leucospilota Polysaccharides (HLP) in Ulcerative Colitis

Scope Holothuria leucospilota polysaccharides (HLP) are bioactive polysaccharides with immunomodulatory effects. This study aims to investigate the impact of HLP on dextran sodium sulfate (DSS)‐induced colitis in rats and further investigate the complex interactions between changes in intestinal microbiota, cometabolites, and intestinal inflammation under HLP intervention. Methods and results The ulcerative colitis (UC) model of Sprague Dawley (SD) rats is established by a normal diet with 3%DSS. The effects of HLP on UC are studied by gavage of different doses of HLP for 2 weeks. The results show that HLP alleviate the inflammation of UC and reduce histological damage and secretion of tumor necrosis factor‐α (TNF‐α), IL‐6, IL‐1β, and IL‐10. After HLP treatment, the intestinal flora of UC rats is regulated, and the flora diversity is restored. Fecal metabolomics analysis reveal the modulatory effects of HLP on amino acid metabolism, antimicrobial peptide anabolism, and energy metabolism in rats with colitis. Correlation analysis of microbial and intestinal metabolites reveals the potential mechanism of HLP affecting colitis. Conclusion HLP repair the intestinal compartment's metabolic disorder by regulating intestinal flora's structure and alleviating colonic mucosal injury and inflammation in colitis rats. This study investigates the preventive and ameliorative effects of Holothuria leucospilota polysaccharides (HLP) on ulcerative colitis (UC). The regulation mechanism of HLP on intestinal flora and metabolites in colitis rats is analyzed. This study provides new ideas for analyzing the intestinal flora–metabolite–host phenotype axis and microbial interactions in UC and clinical treatment.