Our research focuses on how bacterial cells sense mammalian neurotransmitters to gage the physiological and immune state of the host, leading to reprogramming of bacterial transcription towards host and niche adaptation. We have also identified several bacterial adrenergic, endocannabinoid and serotonergic receptors. We have shown that these bacterial neurotransmitter receptors also sense bacterial signals, such as the novel pirazynone family of autoinducer-3 (AI-3) autoinducers, and indole, which in turn influence mammalian cell signaling, linking inter-kingdom chemical communication at the biochemical level. These studies highlight the co-evolution and the fundamental relationship between mammals and microbes. We reported that invading pathogens can hijack these inter-kingdom signaling systems to promote virulence expression. We translated these basic science concepts into strategies to develop a novel approach to anti-virulence therapies. Moreover, we have shown that enteric pathogens exploit nutritional cues (Carbon, aminoacids and/or nitrogen sources) made available by the gut microbiota and the host as signals to coordinate virulence regulation and modify the pathogen’s metabolism allowing for efficient host colonization. Finally, the cross-signaling with neurotransmitters, which is a key event in the gut-brain-axis, can also lead to new insights into drug addiction, and repurposing of agonists and antagonists of the adrenergic, serotonergic and endocannabinoid systems as potential novel anti-bacterial therapies.