Neuroscience, immunology and microbiome research are all converging in an emerging interdisciplinary field of profound significance for biomedicine and basic biology. While the brain–immune axis is now beginning to be considered as a dynamic information-processing system, many gaps exist in our understanding of the functional links between the brain, immunity, and microbes. Here, we use a unique amphibian brainless model, in which Xenopus laevis embryos develop without a brain but with intact spinal cord, to reveal the role of the brain in regulating the early innate immunity in the presence or absence of infection. Our morphological and transcriptional analyses show that the nascent brain has significant control over the response of the innate immune system. We demonstrate that the presence of the brain increases the survival rate of Xenopus embryos after bacterial infection with pathogenic E. coli, through effects on macrophage migration and the transcriptional networks related to innate immunity. In addition, we reveal a rich dataset of transcripts involved in brain-dependent and brain-independent regulation of the infection response. To guide investigation of brain-bacteria communication in a powerful in-vitro model, we are developing the first integrated electrical-optical brain-bacteria interface (BBI), a multi-site stimulation and recording platform specifically suited to extract information in real-time across highly diverse biological entities. Here, we show real-time information transfer in co-culture of neurons and bacteria, both optically, through fluorescent genetically-encoded ion reporters, and electrically, through customized micro-electrode-array on microfluidic chambers. The extraction of information content from signaling between neurons and pathogens will produce new knowledge of both basic and applied (biomedical) impact, bridge a capabilities gap that establishes a new direction for neuroscience and immunology, and serve as an enabling technology that many other labs will be able to use to addressing major challenges (from cellular/molecular neuroscience to disease modelling).