It is known that the gut microbiota can affect the normal physiology of the gastrointestinal tract and liver. Further, disturbances of the microbiota community structure from both endogenous and exogenous influences as well as the failure of host responsive mechanisms have been implicated in a variety of disease processes. Mechanistically, alterations in intestinal permeability and dysbiosis of the microbiota can result in inflammation, immune activation, and exposure to xenobiotics. In addition, the gut and liver are continually exposed to small molecule products of the microbiota with proinflammatory, gene regulatory, and oxidative properties. Long-term coevolution has led to tolerance and incorporation of these influences into normal physiology and homeostasis; conversely, changes in this equilibrium from either the host or the microbial side can result in a wide variety of immune, inflammatory, metabolic, and neoplastic intestinal and hepatic disorders. This seminar will discuss three related topics, including the identification of the microbial metabolite delta-valerobetaine as a diet-dependent obesogen, how supplementation with the gut microbe generated metabolite butyrate to pregnant mice elicits cytoprotection against colonic injury in offspring, and how supplementation with a novel probiotic protects against gut injury via TLR2/Myd88-mediated signaling.