Human disease is affected by diet, as well as by the composition of the gut microbiota, through poorly understood mechanisms. One of the major activities of commensal microbes is digestion of dietary fibre to yield short chain fatty acids (SCFAs). Deficiency of dietary fibre, in particular, has been associated with increased mortality due to various diseases. Decreasing amounts of fibre intake in western countries is one hypothesis for the increased incidences of certain inflammatory diseases. SCFAs affect numerous biological systems, either through stimulation of ‘metabolite-sensing’ G-protein coupled receptors or through inhibition of histone deacetylases (HDACs). We found that diets deficient in fibre produced marked alterations in the composition of the gut microbiota in mice, and led to exacerbated disease in models of intestinal injury and inflammation, colon cancer, type 1 diabetes, asthma, and wound healing. In contrast, very high intake of dietary fibre protected against these conditions. The burring questions in the field of dietary metabolites to be addressed in future studies are: What is the relative importance of metabolite-sensing GPCRs versus HDACs for gut health and human disease? How important are metabolites such as SCFAs for a ‘developmental origin’ of disease, i.e. diseases that are put in train in utero or during breast feeding, and which may have an epigenetic basis? What are all the metabolites of beneficial bacteria, and are non-bacterially produced metabolites important as well?