Hypsizygus marmoreus polysaccharides protect against cisplatin-induced intestinal mucositis via modulation of gut microbiota, inflammation, and intestinal barrier function

Introduction Chemotherapy-induced intestinal mucositis is a frequent and debilitating complication of anticancer treatment, particularly with cisplatin, leading to disruption of the epithelial barrier, inflammation, and dysbiosis of the gut microbiota. Natural polysaccharides with antioxidant and immunomodulatory properties have attracted increasing attention as potential protective agents. This study investigated the protective effects of Hypsizygus marmoreus polysaccharides (HMP) against cisplatin-induced intestinal mucositis in mice. Methods HMP were extracted and structurally characterized through monosaccharide composition and molecular weight analysis. Antioxidant activity was evaluated using the ABTS + radical-scavenging assay. A cisplatin-induced mucositis mouse model was established to assess the protective effects of HMP on clinical symptoms, intestinal histopathology, inflammatory cytokines, epithelial barrier integrity, and gut microbiota composition using 16S rRNA sequencing. Results HMP were obtained at a yield of 16% and consisted mainly of glucose (52.44%) and galactose (21.05%), together with other monosaccharides, with a molecular weight of 752.96 kDa. In vitro , HMP exhibited concentration-dependent antioxidant activity, with ABTS + radical-scavenging increasing from 36.2% at 0.25 mg/mL to nearly 100% at≥20 mg/mL. In vivo , cisplatin administration induced body weight loss, diarrhea, immune organ atrophy, intestinal epithelial damage, and gut microbiota dysbiosis. HMP treatment significantly alleviated these alterations, improved intestinal histological structure, enhanced tight junction protein expression and mucin secretion, suppressed pro-inflammatory cytokines including IL-1β, IL-6, and TNF- α , and restored microbial diversity. Notably, beneficial taxa such as as Akkermansia muciniphila and Bifidobacterium pseudolongum were enriched following HMP administration. Discussion These findings indicate that HMP protects against cisplatin-induced intestinal mucositis through multiple complementary mechanisms, including antioxidant activity, suppression of inflammatory responses, preservation of epithelial barrier integrity, and modulation of gut microbiota composition. HMP therefore represents a promising natural candidate for mitigating chemotherapy-induced gastrointestinal toxicity.