Nutritional regulation of gut-brain immune crosstalk across the lifespan

The gut-brain immune axis integrates microbial, immune, and neural signals to regulate neurodevelopment, homeostasis, and disease susceptibility. Early-life nutrition, particularly human milk oligosaccharides, shapes beneficial microbiota composition, enhances hippocampal plasticity, promotes anti-inflammatory microglia polarization, and fosters immune tolerance. Gut microbiota-derived metabolites, including short-chain fatty acids, tryptophan derivatives and secondary bile acids, regulate microglia maturation, astrocyte function, T cell differentiation, neurotransmitter production, and vagus nerve signaling. These processes influence synaptic pruning, neurogenesis, and neuroinflammation. Adaptive immune cells in the central nervous system, notably meningeal and infiltrating CD4 T cells, further connect peripheral immunity to neuronal responses through cytokines, such as IL-4, IFNγ, and IL-17A. Nutritional imbalances may exacerbate disease-associated microglia and pathogenic T cell activity in Multiple Sclerosis, Alzheimer's disease, and autism spectrum disorders. In aging, diet helps mitigate "inflammaging" by countering metabolic shifts in microglia and lymphocytes. This review examines how nutrition modulates bidirectional gut-brain immune crosstalk across the lifespan.