© Copyright © 2020 Sharma, Li, Stoll and Tollefsbol. Metabolic diseases are becoming an alarming health issue due to elevated incidences of these diseases over the past few decades. Various environmental factors are associated with a number of metabolic diseases and often play a crucial role in this process. Amongst the factors, diet is the most important factor that can regulate these diseases via modulation of the gut microbiome. The gut microbiome participates in multiple metabolic processes in the human body and is mainly responsible for regulation of host metabolism. The alterations in function and composition of the gut microbiota have been known to be involved in the pathogenesis of metabolic diseases via induction of epigenetic changes such as DNA methylation, histone modifications and regulation by noncoding RNAs. These induced epigenetic modifications can also be regulated by metabolites produced by the gut microbiota including short-chain fatty acids, folates, biotin and trimethylamine-N-oxide. In addition, studies have elucidated the potential role of these microbial-produced metabolites in the pathophysiology of obesity and diabetes. Hence, this review focuses on the interactions between the gut microbiome and epigenetic processes in the regulation and development of obesity and diabetes, which may have potential as a novel preventive or therapeutic approach for several metabolic and other human diseases.