The microbial community of the gastrointestinal tract and the central nervous system communicate via a bidirectional network of signaling pathways known as the gut-brain axis. This axis has emerged as a complex regulator of system-wide physiology, playing essential roles in the outcomes of metabolic and neurological diseases. Thus far, most gut-brain axis mechanisms are described as indirect via bacterial interaction with, for example, the immune system or the vagus nerve. However, microbe-derived compounds are found in the brain, where these compounds can interact directly with neurons, in a direct gut-brain axis mechanism. My work was one of the first to highlight that brain neurons responded via a direct mechanism to microbe-derived compounds in an interaction that was sex- and age-dependent. However, the limited knowledge of how these compounds reach the brain, whether the gut-brain axis is affected by the individual’s physiological state (e.g. hormonal status) and its impact on the host, impairs advances for understanding host-microbe interactions and translational approaches. Therefore, this project is set up to unveil the trafficking mechanisms of gut-derived compounds to the brain and to dissect how physiological factors influence microbe-induced neuronal activation. Furthermore, this project may lead to the description of novel neuroactive microbe-derived compounds, describing their effects on the host’s metabolism and behavior. This work will advance the knowledge of how gut-commensal bacteria can interact with brain neurons, regulating host physiology and the factors that impact this interaction. This new knowledge will be a major step towards understanding novel aspects of host-microbial symbiotic relationships, opening new possibilities for developing individual-specific treatments for neurometabolic diseases and beyond.
