Background The effects of β-glucan on colitis mice are contradictory in previous reports. As a result, it is still unclear whether there is an anti-colitis effect in Ganoderma lucidum polysaccharide (GLP), which is mainly composed of β-glucan. Moreover, the association between GLP function and gut microbiota remains to be elucidated. Objective This study aimed to investigate whether GLP consumption improved rat dextran sodium sulfate (DSS)-induced colitis by regulating gut microbiota and altering colonic epithelial expression. Design The disease activity index (DAI) scores and the cecal short chain fatty acid (SCFA) levels of DSS-induced colitis rats fed with a GLP diet (Group GLP, n = 6) and a control diet (Group Con, n = 6) were investigated and analyzed. Moreover, the profiles of gut microbiota and colonic epithelial expression were analyzed using metagenomics and transcriptomics. Results GLP consumption significantly lowered animal DAI scores by producing more SCFAs by increasing SCFA-producing bacteria such as Ruminococcus_1 and reducing pathogens such as Escherichia-Shigella in both the small intestine and cecum of rat. Moreover, GLP consumption regulated 11 genes, including six upregulated ( Ccl5 , Cd3e , Cd8a , Il21r , Lck , and Trbv ) and five downregulated ( Ccl3 , Gro , Il11 , Mhc2 , and Ptgs ) genes enriched in six inflammation-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, resulting in enhancement of immunity and reduction of inflammatory response and colonic cancer risk. Conclusions GLP consumption alleviated DSS-induced colitis and may have potential for ulcerative colitis relief.

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