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Gut microbiota and its metabolites, along with host metabolism of ʟ-carnitine, play a crucial role in cardiovascular disease (CVD) development, forming Trimethylamine-N-oxide (TMAO), an atherosclerosis risk factor. TMAO promotes the formation of atherosclerotic plaques and platelet aggregation potential, causing thrombosis. A high-fat diet and carnitine administration can accelerate CVD progression. Ginger (Zingiber officinale Roscoe) essential oil (GEO) and its bioactive compound citral have lipid lowering and anti-inflammatory effects, which may prevent CVD; however, their ability to prevent atherosclerosis through gut microbiota modulation remains to be elucidated. Furthermore, the Gubra Amylin NASH (GAN) diet is a palm oil-containing high-fat diet for inducing steatohepatitis; however, the study of the GAN diet in combination with ʟ-carnitine for inducing atherosclerosis in mouse model has not been investigated yet. We examined the CVD-protecting effect of GEO and citral against the formation of aortic atherosclerosis and linked them with changes in the gut microbiota and its metabolites in the ʟ-carnitine/GAN diet-treated apolipoprotein E-deficient (ApoE−/−) mouse model. GEO and citral demonstrated CVD protective function by alleviating aortic atherosclerotic lesions. They reduced blood sugar, improved insulin resistance, decreased plasma TMAO levels, and inhibited serum inflammatory cytokines, especially interleukin-1β. Moreover, they demonstrated their ability to modulate gut microbiota diversity and composition into a favourable direction. Collectively, GEO and citral may serve as potential prebiotics for CVD prevention by improving dysbiosis.

Diet and gut microbiota contribute to non-alcoholic steatohepatitis (NASH) progression. High-fat diets (HFDs) change gut microbiota compositions and induce gut dysbiosis and intestinal barrier leakage, which facilitates portal influx of pathogen-associated molecular patterns [e.g., lipopolysaccharides (LPS)] to the liver and triggers inflammation in NASH. The current therapeutic drugs for NASH have adverse side effects; however, several foods and herbs have exhibited hepatoprotection. We investigated ginger essential oil (GEO) against palm oil-containing HFDs in LPS-injected murine NASH model. GEO prevented NASH development by increasing plasma alanine aminotransferase levels; increasing antioxidant catalase, glutathione reductase, and glutathione levels; and reducing hepatic pro-inflammatory cytokine levels. GEO alleviated hepatic inflammation through mediated NLR family pyrin domain-containing 3 inflammasome and LPS/Toll-like receptor 4 signaling pathways. GEO further increased beneficial bacterial abundance and reduced NASH-associated bacterial abundance. GEO may, therefore, prevent NASH by inhibiting hepatic inflammation and modulating the gut microbiota and its metabolite-related pathway.

A high-fat diet (HFD) animal model has an indispensable role in the research of gut-liver axis by generating an imbalance of gut microbiota and intestinal leakage, resulting in translocation of harmful bacterial metabolites and lipopolysaccharides (LPSs) to the liver, triggering immune responses, and stimulating non-alcoholic steatohepatitis (NASH). Replacing trans-fat with palm oil in HFDs is an emerging animal model with human translatability in terms of liver biopsy phenotype and transcriptome changes. We developed the NASH and fibrosis mouse model using a palm oil-containing high-fat diet (P-HFD) combined with LPS to simulate gut dysbiosis and endotoxemia and examined the role of carbon tetrachloride (CCl4) on the gut-liver axis. The mice were fed P-HFD with or without intraperitoneal LPS/CCl4 injections. NASH/fibrosis progression and gut microbiota shift were examined at 4, 8, 12, 16, 20, and 24 weeks (n = 192). The P-HFD animal model showed obesogenic and metabolic changes, hepatomegaly, NASH phenotype, increased gut dysbiosis, changes in gut microbiota and its function, reduced beneficial bacteria, increased pathogenic related microbiome, intestinal leakage, and endotoxemia. P-HFD with LPS supplementation resulted in comparable NASH phenotypes compared with the P-HFD group, but worsened the degree of intestinal microbiota dysbiosis by increasing the occurrence of pathogenic bacteria and reducing beneficial microbiota. P-HFD with CCl4 resulted in a liver fibrosis phenotype and produced a more severe gut microbiota shift. These mouse models could be informative for a researcher focused on the gut-liver axis and could be used as valuable tool for preclinical drug testing.

Animal models of non-alcoholic steatohepatitis (NASH) and liver fibrosis are essential for preclinical research of novel drugs. A high-fat diet (HFD) animal model has an indispensable role in the research of gut-liver axis by generating an imbalance of gut microbiota and intestinal leakage, resulting in translocation of harmful bacterial metabolites and lipopolysaccharides (LPSs) to the liver, triggering hepatic immune responses, and stimulating NASH and liver fibrosis. Replacing trans-fat with palm oil in HFDs is an emerging animal model with human translatability in terms of liver biopsy phenotype and transcriptome changes. We developed the NASH and fibrosis C57BL/6J mouse model using a palm oil-containing high-fat diet (P-HFD) combined with LPS to simulate gut dysbiosis and endotoxemia and examined the role of carbon tetrachloride (CCl4) on the gut-liver axis. We developed the mouse models, and the mice were fed P-HFD with or without intraperitoneal LPS/CCl4 injections. NASH/fibrosis progression and gut microbiota shift were examined at 4, 8, 12, 16, 20, and 24 weeks (n=192). The animal model showed obesogenic and metabolic changes, hepatomegaly, increased hepatic lipid levels, NASH phenotype, increased gut dysbiosis, changes in gut microbiota and its function, reduced beneficial bacteria, increased pathogenic related microbiome, intestinal leakage, and endotoxemia. P-HFD with LPS supplementation resulted in comparable NASH, intestinal leakage, and endotoxemia phenotypes compared with the P-HFD group, but worsened the degree of intestinal microbiota dysbiosis by increasing the occurrence of pathogenic bacteria and reducing beneficial microbiota. P-HFD with CCl4 resulted in a liver fibrosis phenotype and produced a more severe gut microbiota shift. These mouse models could be informative for a researcher focused on the gut-liver axis and could be used as valuable tool for preclinical drug testing.