Gut dysbiosis might underlie the pathogenesis of numerous diseases. We have found that key features of several diseases correlate inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Feeding mice acetate- and butyrate-yielding diets provided a surprisingly high degree of protection, in models of colon cancer, as well as type 1 diabetes, food allergy, colitis, hypertension, and asthma. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas both acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of inflammatory cytokines. We have identified several cellular and molecular pathways whereby metabolites provide beneficial effects in disease models, including colon cancer. These include signalling through ‘metabolite sensing’ GPCRs such as GPR43, and inhibition of HDACs. Medicinal foods or metabolites might represent an effective and natural approach for countering numerous defects that contribute to human diseases. Such an approach may be useful in combination with checkpoint inhibitors, for human cancers.