The prevalence of metabolic diseases, including obesity, dyslipidemia, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD), is a severe burden in human society owing to the ensuing high morbidity and mortality. Various factors linked to metabolic disorders, particularly environmental factors (such as diet and gut microbiota) and epigenetic modifications, contribute to the progression of metabolic diseases. Dietary components and habits regulate alterations in gut microbiota; in turn, microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), are influenced by diet. Interestingly, diet-derived microbial metabolites appear to produce substrates and enzymatic regulators for epigenetic modifications (such as DNA methylation, histone modifications, and non-coding RNA expression). Epigenetic changes mediated by microbial metabolites participate in metabolic disorders via alterations in intestinal permeability, immune responses, inflammatory reactions, and insulin resistance. In addition, microbial metabolites can trigger inflammatory immune responses and microbiota dysbiosis by directly binding to G-protein-coupled receptors (GPCRs). Hence, diet-gut microbiota-epigenetics may play a role in metabolic diseases. However, their complex relationships with metabolic diseases remain largely unknown and require further investigation. This review aimed to elaborate on the interactions among diet, gut microbiota, and epigenetics to uncover the mechanisms and therapeutics of metabolic diseases.

Background Atherosclerosis is a widely studied pathophysiological foundation of cardiovascular diseases. The gut microbiota and their metabolites are considered independent risk factors for atherosclerosis. Polydatin combined with hawthorn flavonoids (PH), as the extracts of Polygonum cuspidatum Sieb. et Zucc. (P. cuspidatum) and Crataegus pinnatifida Bunge (C. pinnatifida), have shown excellent cardiovascular protective effects. However, the underlying mechanism requires further investigation. Our study aimed to explore the anti-atherosclerotic mechanism of PH through gut microbiota and their metabolites. Methods ApoE^−/− mice were fed either a normal-chow diet or a high-fat diet. The PH group received varied doses of polydatin and hawthorn flavonoids: a high dose (polydatin 200 mg/kg daily; hawthorn flavonoids 100 mg/kg daily), a medium dose (polydatin 100 mg/kg daily; hawthorn flavonoids 50 mg/kg daily), and a low dose (polydatin 50 mg/kg daily; hawthorn flavonoids 25 mg/kg daily). The control and model groups were administered distilled water (0.2 mL daily). The experiment lasted for 24 weeks. Results PH administration significantly reduced lipid and inflammatory cytokine levels, meanwhile, the atherosclerotic lesions in a high-fat diet-induced ApoE^−/− mice were significantly decreased. Additionally, PH also inhibited the enhancement of trimethylamine N-oxide (TMAO), trimethylamine (TMA) levels of HFD-induced ApoE^−/− mice by regulating the expression of hepatic flavin-containing enzyme monooxygenase 3 (FMO3). 16S rRNA sequencing results demonstrated that high-dose PH treatment reduced Firmicutes/Bacteroidetes ratio, increased the abundance of Actinobacteriota, Atopobiaceae and Coriobacteriaea_UCG-002, and decreased the abundance of Desulfobacterota. Norank_f_Muribaculaceae was enriched in the medium-dose PH and simvastatin groups, and Lactobacillus was mainly increased in the simvastatin and the low-dose PH groups. According to the metagenetic results, functional annotations also suggested that the biological processes of each group mainly focused on metabolism-related processes. Specifically, PH may regulate the abundance of TMA-producing bacteria (Coriobacteriaceae, Desulfovibrio, Muribaculum, and Clostridium) and related enzymes in glycolipid metabolic pathways to exert an important effect on the prevention of atherosclerosis. Conclusions Our results suggested that PH could regulate the glucolipid metabolism-related pathway, attenuate inflammatory cytokine levels, and reduce atherosclerotic plaques by remodeling gut microbiota. Trial registration: Not applicable.