The human gut microbiome includes trillions of bacteria colonizing the intestinal tract. These bacteria exist in close contact with the intestinal epithelial barrier, composed of a single layer of cells separating the lumen from the immune-cell rich lamina propria and the rest of the body. It has become evident that inflammation and perturbations to immune homeostasis associated with diseases such as inflammatory bowel diseases (IBDs), as well as disruptions in our gut due to infection with pathogenic microbes, can lead to a myriad of functional changes in terms of intestinal permeability and physiology. We have determined that three gut microbially-produced, dietary-derived metabolites activate host receptors and affect downstream host proteins to protect the host during inflammation associated with IBDs as well as during infection with the human pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 and the murine pathogen Citrobacter rodentium. These metabolites can improve intestinal barrier function and mediate colonization resistance against pathogens. We envision that our findings hold great promise for potential prophylactic or therapeutic treatments for host intestinal ailments.