Abstract
The diversity of the bacterial community in the gut is closely related to human health. Gut microbes accomplish multiple physiological and biochemical functions. Sitosterols are a series of phytochemicals that have multiple pharmacological activities and are used as cholesterol-lowering drugs in clinical practice. In this study, we investigated the roles of bacteria and short-chain fatty acids (SCFAs) to the anti-colorectal cancer (anti-CRC) effects of sitosterols in BALB/c nude mice. Sitosterols were administered orally and gut microbiota composition and intestinal SCFAs changes were analyzed. The correlation between gut microbiota, SCFAs, and tumor apoptosis was assessed by a series of in vivo and in vitro experiments. Tumor growth in the mice was inhibited by sitosterol-treatment. Mechanistic studies revealed that sitosterol-treatment reduced the expression of PI3K/Akt, promoted the activation of Bad, decreased Bcl-xl, and enhanced cyto-c release, leading to caspase-9 and caspase-3 activation, PARP cleavage, and apoptosis. 16S rDNA analysis revealed that the diversity of microbiota, particularly phyla Bacteroidetes and Firmicutes, reduced dramatically in the gut of tumor-bearing mice, whilst treatment with sitosterols reversed these changes. The levels of SCFAs in the fecal samples of sitosterol-treated mice increased, leading to cancer cell apoptosis in vitro. Moreover, tumor apoptosis was induced after mice received a daily dose of 2 × 108 CFU/0.2 mL Lactobacillus pentosus or 20 mM/0.2 mL SCFAs. Taken together, these results demonstrate that sitosterols maintain a diverse microbial environment and enrich the content of L. pentosus in the gut, leading to the production of beneficial metabolites including SCFAs that promote tumor apoptosis.