The consumption of unbalanced diets, rich in sugars and saturated fats, is a determinant risk factor for the development of metabolic and cardiovascular diseases, as well as susceptibility to emotional and cognitive disorders. Evidence suggests that intestinal dysbiosis (alteration of microbiota composition and diversity) induced by dietary dysregulation impacts the intercommunication of the gut-adipose tissue-brain axis, leading to metabolic dysfunctions and brain damage. Our hypothesis is that bioactive metabolites produced by adipose tissues and the microbiota, under dysfunctional metabolic conditions, may interact with specific receptors (GPRs), both peripherally and in the brain, regulating pro-inflammatory processes. On the other hand, dietary, probiotic, and thermogenic manipulations generate pro-resolutive metabolites to control inflammation. Microglia, vital for the development and homeostasis of the Central Nervous System (CNS), act as immune sensors of the brain, responsive to these metabolites, and therefore, protagonists in neuroimmune signaling and amenable to resolutive manipulations. We intend to delineate immune-microbiome interactions under healthy or metabolically disordered conditions, as well as to evaluate their effects on metabolic dysfunction, cognitive impairment, and neuroimmune modulation in mice. For that, we have set up a set of experimental protocols for metabolic disorders, employing dietary, (chemo)genetic, and thermogenic techniques to identify a microbiome signature capable of modulating metabolic and inflammatory signaling in the CNS. This proposal will generate integrated data on key issues related to the gut-brain axis and communication through bioactive mediators. The results of our study will be crucial in supporting clinical guidelines and therapeutic interventions aimed at controlling neurodegeneration and, consequently, susceptibility to dementia.