Abstract: With the grape seed polyphenols as research object, an immunosuppressive mice model was established through cyclophospamide（CPA） induction, and Illumina Mi Seq high-throughput sequencing platform was used to explore the effect of grape seed polyphenols on the gut microbiota in immunosuppressive mice. The results showed that the grape seed polyphenols intervention could increase the immune organ index and the content of immunoglobulin（sIgA, IgM, IgG） in mice. Furthermore, the low does grape seed polyphenols could increase the diversity of gut microbiota, and promote the growth of Lactobacillus, Bacteroides, Parabacteroides distasonis, Bifidobacterium, Turicibacter, Alloprevotella tannerae, Allobaculum and Romboutsia, and inhibit the growth of Barnesiella, Escherichia/Shigella, Akkermansia. Meanwhile, the proliferation of probiotics such as Lactobacillus and Bifidobacterium was conducive to promoting the production of short-chain fatty acids, thus enhancing the immune ability of the body.