Recent studies highlight the profound effects of diet, gut microbiota, and bacterial metabolites on various systems, including obesity, inflammation, and other ‘western lifestyle’ diseases. Diet affects the composition and diversity of the gut microbiota, which in turn regulates gut homeostasis. There are 2 main mechanisms- bacterial or dietary metabolites engage ‘metabolite-sensing’ G-protein coupled receptors (GPCRs). For instance short chain fatty acids (SCFAs) bind GPR43, GPR41 and GPR109A. SCFAs also influence gene transcription and epigenetics through inhibition of histone deacetylases (HDACs) which regulate the function of certain transcription factors, notably FoxP3. It is becoming clear that numerous metabolites regulate immunity, in particular SCFAs, omega-3 fatty acids, and tryptophan metabolites. Insufficient intake of fiber or other healthy foodstuffs likely affects gut microbial ecology and the production of particular metabolites, which alters immune regulation and development of inflammatory disorders. These dietary effects may occur in utero, during lactation, and at other times through life, and involve both immediate type effects through metabolite-sensing GPCRs, or epigenetic effects that manifest over decades or generations.