The human gastrointestinal (GI) tract is colonized by approximately 1014 bacterial cells that co-exists with the host. The GI tract microenvironment contains a broad range of range molecules, including quorum sensing signals and metabolites produced by the resident microbiota, and hormones like norepinephrine and dopamine that are synthesized locally in the GI tract by the enteric nervous system. The close proximity of bacteria and the host cells, as well as the abundance of the signals they secrete, has led to the emergence of a new paradigm in which molecules produced by the host are recognized by the bacteria and vice-versa. The microbiota and the host not only recognize non-canonical molecules but can also further modify them to generate small molecules with a broad range of structural and functional diversity. Our central hypothesis is that inter-domain signaling between bacteria and host cells is a key determinant of homeostasis and disease in the GI tract. Specifically, we are investigating the role of these interactions in the sensing and migration of pathogens during infections, in the spatial organization and localization of bacterial communities, and in the modulation of host inflammatory signaling. In this talk, I will discuss our recent work on elucidating the role of microbiota-derived small molecules on inflammatory signaling and metabolomics approaches for discovery of bioactive microbiota-derived molecules in the GI tract.