Fecal metagenome and plasma metabolome analyses reveal changes in gut microbiota composition and plasma metabolites in rats with abemaciclib-induced diarrhea

Abstract Abemaciclib-induced diarrhea is a common side effect of HR+/ HER2− breast cancer treatment. The aim of this study was to explore changes in gut microbiota composition and plasma metabolites in rats with abemaciclib-induced diarrhea. Female rats were randomly divided into abemaciclib (orally administered abemaciclib, n = 11) and control (orally administered 0.9% saline, n = 6) groups. When the rats reached grade 3 diarrhea, the jejunum, ileum, and colon tissues were collected for histological analysis to assess intestinal mucosal damage. Rat feces were obtained for metagenomic analysis to analyze changes in the gut microbial composition. Rat plasma was used for untargeted metabolomic analysis to analyze plasma metabolic alterations. Pearson’s correlation analysis was conducted to examine the association between differential gut microbiota and differential plasma metabolites, and a microbiota-metabolite-pathway network was constructed. Rats in the abemaciclib group developed noticeable diarrhea and exhibited histopathological changes in the ileal epithelium and jejunum. The alpha diversity indices significantly decreased in the abemaciclib group. Firmicutes, Bacteroidetes, and Proteobacteria were the most abundant phyla in all groups. Compared with the control group, the abundance of Firmicutes remarkably decreased in the abemaciclib group, whereas that of Proteobacteria and Verrucomicrobia dramatically increased. Differentially enriched species in the abemaciclib group included Escherichia coli, Butyricimonas virosa, Desulfovibrionaceae bacterium, and Helicobacter ganmani. Functional analysis showed that pathways related to carbohydrate metabolism were significantly altered. Additionally, 319 metabolites were differentially expressed between the two groups, including trimethylamine N-oxide, sarsasapogenin, tyrosol, brinzolamide, and cis-3-hexenyl acetate. Multiple pathways, including mTOR signaling pathway, were significantly enriched by differential metabolites. Furthermore, close associations between differential microbiota and metabolites were observed, and numerousmicrobiota-metabolite-pathway axes were identified, such as Pseudodesulfovibrio mercurii/Desulfovibrionaceae bacterium-cis-3-hexenyl acetate-alpha-linolenic acid metabolism. Our findings revealed that abemaciclib alters the gut microbiota composition, plasma metabolites, and their related metabolic pathways. These changes contribute to abemaciclib-induced diarrhea and may provide promising therapeutic targets for managing this disorder in rats.