The microbiota controls host physiology at multiple levels. Microbial metabolic products such as SCFAs bind to GPCRs on intestinal epithelial cells (for example, Gpr41 and Gpr43) to control energy balance, partly via the gut-derived hormone Pyy, and also to control the inflammatory responsiveness of the host. Tlr5 activation (e.g., through bacterial flagellin) presumably on epithelial or myeloid cells profoundly affects the structural composition of the intestinal microbiota, which in turn regulates appetite, weight gain, and insulin sensitivity through unknown mechanisms. Microbial signals also regulate Fiaf release from intestinal epithelial cells, which acts as an inhibitor of Lpl and thereby regulates peripheral fat storage. Through another unknown mechanism, the microbiota also regulates the energy gauge in the liver and muscle through the phosphorylation of Ampk. Glp2 ascertains epithelial barrier function, and a leaky barrier leads to exposure and activation of myeloid cells in response to microbial signals such as the Tlr4 ligand endotoxin. Fiaf, fasting-induced adipose factor; Glp2, glucagon-like peptide-2; Gpr41/43, G-protein coupled receptor; Lpl, lipoprotein lipase; Pyy, peptide YY; SCFA, short chain fatty acids.