The Potential Role of Intestinal Microbiota on the Intestine-Protective and Lipid-Lowering Effects of Berberine in Zebrafish (Danio rerio) Under High-Lipid Stress

Background: Berberine has extremely low oral bioavailability, but shows a potent lipid-lowering effect, indicating its potential role in regulating intestinal microbiota, which has not been investigated. Methods: In the present study, five experimental diets, a control diet (Con), a high-lipid diet (HL), and high-lipid·diets·supplemented with an antibiotic cocktail (HLA), berberine (HLB), or both (HLAB) were fed to zebrafish (Danio rerio) for 30 days. Results: The HLB group showed significantly greater weight gain and feed intake than the HLA and other groups, respectively (p < 0.05). Hepatic triglyceride (TG) and total cholesterol (TC) levels, lipogenesis, and proinflammatory cytokine gene expression were significantly upregulated by the high-lipid diet, but significantly downregulated by berberine supplementation. Conversely, the expression levels of intestinal and/or hepatic farnesoid X receptor (fxr), Takeda G protein-coupled receptor 5 (tgr5), lipolysis genes, and zonula occludens 1 (zo1) exhibited the opposite trend. Compared with the HLB group, the HLAB group displayed significantly greater hepatic TG content and proinflammatory cytokine expression, but significantly lower intestinal bile salt hydrolase (BSH) activity and intestinal and/or hepatic fxr and tgr5 expression levels. The HL treatment decreased the abundance of certain probiotic bacteria (e.g., Microbacterium, Cetobacterium, and Gemmobacter) and significantly increased the pathways involved in cytochrome P450, p53 signaling, and ATP-binding cassette (ABC) transporters. The HLB group increased some probiotic bacteria abundance, particularly BSH-producing bacteria (e.g., Escherichia Shigella). Compared with the HLB group, the abundance of BSH-producing bacteria (e.g., Bifidobacterium and Enterococcus) and pathways related to Notch signaling and Wnt signaling were reduced in the HLAB group. Conclusions: This study revealed that berberine’s lipid-lowering and intestine-protective effects are closely related to the intestinal microbiota, especially BSH-producing bacteria.