Diet-gut microbiota-epigenetics in metabolic diseases: From mechanisms to therapeutics

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.