Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa. Risk of colorectal cancer in ulcerative colitis is increased in patients with long-standing disease compared with the general population. Hericium erinaceus (HE) has been used in traditional folk medicine and medicinal cuisine in China, Korea and Japan with anti-gastritis and anti-ulcerative colitis activities. EP-1, a purified unique polysaccharide isolated from HE mycelium, has recently been identified as the active component responsible for anti- ulcerative colitis activity by using a cell model for identification. In this study, our data shows that EP-1 was effective in relieving the symptoms of acetic acid induced UC rats. Based on the Illumina MiSeq platform, 16S rRNA sequencing of the rat colonic contents indicated that the intestinal flora structure remarkably changed in the model rats and the tendency was alleviated to a certain degree by EP-1. The further results showed that in the acetic acid induced UC rats EP-1 modulated the gut microbiota community and increased short chain fatty acids (SCFAs). And immunoblot analyses showed that after treated by EP-1, GPR41 and GPR43 were significantly suppressed expression in colonic tissues of the UC rats. In the meanwhile, EP-1 also showed its antioxidant, anti-inflammatory and enhancing immune activities. Thus, the polysaccharide purified from HE showed potential for anti-UC activity and the complementary and alternative medicine (CAM) herb therapy.