Abstract: OBJECTIVE To investigate the mechanism of total saponins of Panacis Japonici Rhizoma on regulating the number of secretory cells of small intestinal epithelium in mice fed with high fat diet. METHODS Forty Balb/c mice were randomly divided into following 4 groups:control group, high-fat-diet model group, high and low dose of total saponins of Panacis Japonici Rhizoma groups. The mice of control group were given normal maintenance feed. Mice of high-fat-diet model group, high and low dose of total saponins of Panacis Japonici Rhizoma groups were given high-fat feed. In addition, mice of high and low dose groups were given 45, 15 mg·kg^-1 of total saponins of Panacis Japonici Rhizoma every day for oral gavage treatment respectively. Meanwhile, the high-fat diet model group and control group was given intragastric administration with normal saline. The frequency of gavage was to give gavage once a day for 6 d in a week. Mice of each group were sacrificed and ileum tissues were taken after feeding for 7 months. HE staining was used to observe ileum pathological changes of each group. Alcian blue staining, periodic acid-schiff staining were used to count ileum goblet cell of mice and fluorescein peach red staining was used to count Paneth cell number of mice. Immunohistochemical staining was used to detect protein expression levels of Lysozyme and HES1. RESULTS Compared with the high-fat-diet model group, high dose of total saponins of Panacis Japonici Rhizoma group decreased villus length-crypt depth ratio and submucosal layer thickness(P < 0.05), increased depth of crypt and inner ring muscle thickness(P < 0.01), increased goblet cell number and protein expression levels of Lysozyme(P < 0.05 or P < 0.001), and down-regulated protein expression levels of HES1(P < 0.01). CONCLUSION Total saponins of Panacis Japonici Rhizoma regulates the number of small intestinal secretory cells by inhibiting the expression of HES1 protein in the small intestine of mice fed with high fat diet.