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Dietary emulsifiers have been linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Hydrophilic (lecithin (LEC), sucrose esters (SUC), carboxymethylcellulose (CMC)) and lipophilic (mono- and diglycerides (MDG)) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study proved that SUC and CMC induced hyperglycemia and hyperinsulinemia. MDG impaired circulating lipid and glucose metabolism. Both hydrophilic and lipophilic emulsifiers changed the intestinal microbiota diversity and induced gut microbiota dysbiosis. Hydrophilic emulsifiers have no impact on mucus–bacterial interactions, whereas MDG tended to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrated the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.

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.

Antibiotics used as growth promoters in livestock and animal husbandry can be detected in animal-derived food. Epidemiological studies have implicated that exposure to these antibiotic residues in food may be associated to childhood obesity. Herein, the effect of exposure to residual dose of tylosin—an antibiotic growth promoter—on host metabolism and gut microbiota was explored in vivo. Theoretical maximal daily intake (TMDI) doses of tylosin were found to facilitate high-fat diet-induced obesity, induce insulin resistance, and perturb the composition of gut microbiota in mice. The obesity-related phenotypes were transferrable to germ-free recipient mice, indicating that the effects of TMDI dose of tylosin on obesity and insulin resistance occurred mainly via alteration of the gut microbiota. Tylosin TMDI exposure restricted to early life, which is the critical period of gut microbiota development, altered the abundance of specific bacteria related to host metabolic homeostasis later in life. Moreover, early-life exposure to tylosin TMDI was sufficient to modify the ratio of primary to secondary bile acids, thereby inducing lasting metabolic consequences via the downstream FGF15 signaling pathway. Altogether, these findings demonstrate that exposure to very low dose of antibiotic residues, whether continuously or in early life, can exert long-lasting effects on host metabolism by altering gut microbiota and its metabolites. Importance Evidence has indicated that chronic exposure to antibiotic residues in food could contribute to obesity. However, few studies have investigated the effect of chronic exposure to very low-dose antibiotic residue in food (~1000-fold lower than the therapeutic dose) on gut microbiota and host metabolism. Our study demonstrates that even with limited exposure in early life, a residual dose of tylosin causes lasting metabolic disturbances through altering gut microbiota and its metabolites. Our findings reveal that the gut microbiota is susceptible to previously ignored environmental factors.

Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE−/−) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.

The capability of gut microbiota in degrading foods and drugs administered orally can result in diversified efficacies and toxicity interpersonally and cause significant impact on human health. Production of atherogenic trimethylamine N-oxide (TMAO) from carnitine is a gut microbiota-directed pathway and varies widely among individuals. Here, we demonstrated a personalized TMAO formation and carnitine bioavailability from carnitine supplements by differentiating individual TMAO productivities with a recently developed oral carnitine challenge test (OCCT). By exploring gut microbiome in subjects characterized by TMAO producer phenotypes, we identified 39 operational taxonomy units that were highly correlated to TMAO productivity, including Emergencia timonensis, which has been recently discovered to convert γ-butyrobetaine to TMA in vitro. A microbiome-based random forest classifier was therefore constructed to predict the TMAO producer phenotype (AUROC = 0.81) which was then validated with an external cohort (AUROC = 0.80). A novel bacterium called Ihubacter massiliensis was also discovered to be a key microbe for TMA/TMAO production by using an OCCT-based humanized gnotobiotic mice model. Simply combining the presence of E. timonensis and I. massiliensis could account for 43% of high TMAO producers with 97% specificity. Collectively, this human gut microbiota phenotype-directed approach offers potential for developing precision medicine and provides insights into translational research.