Previous study have demonstrated that a compound composed of water-soluable?Ganoderma lucidum?polysaccharides?(GLP) and?Polyporus umbellatus?polysaccharides (PUP) in a ratio of 3:1 named GPP enhances innate immune function in mice through enhancing the function of macrophage cells and activity of natural killer (NK) cells. Here in our research, we further investigated the effect of GPP on the diversity and composition of?intestinal flora, and explored its effect on?colitis?model mice. The immunoregulatory verification experiments of GPP were conducted in both normal and DSS-induced mice model. Our research showed that GPP increased the diversity of intestinal microorganisms in mice with the extension of administration time. Daily GPP intake attenuated DSS-induced?colon injury, protected the splenic?lymphocyte proliferation?ability, enhanced the serum?hemolysin?synthesis, and increased peripheral?phagocytes?and NK cell activity in model mice. Comparisons of the predominant gene pathways of the?bacterial microbiota?showed that?DNA repair?and recombination, base?mismatch repair?pathways was stronger in GPP-treatment group than in control group, indicating the possible molecular mechanisms of immune function regulation. Our study showed that GPP regulated immune function in both health and colitis model, and had a positive effect on maintaining intestinal flora?homeostasis.