Mediterranean Diet and Neurodegenerative Diseases: Recent Advances from the Gut-Immune-Brain Axis to...

Neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) are regarded as systemic illnesses, mainly characterized by long-term neuroinflammation, metabolic dysregulation and barrier dysfunction. All these factors interact through the gut-immune-brain axis. The Mediterranean diet, rich in plant-based foods, olive oil, and fish, has been consistently associated with slower cognitive decline and reduced risk of neurodegeneration in observational studies and some clinical trials. This review provides a systems-level synthesis that distinguishes itself from previous narratives by integrating disease-specific mechanistic frameworks with multi-omics-guided precision nutrition strategies. We summarize recent evidence showing that this dietary pattern can remodel gut microbiota composition and enhance the production of bioactive metabolites such as short-chain fatty acids (SCFAs). These metabolites are associated with improved intestinal barrier integrity, reduced systemic inflammation, and potential modulation of brain functions. Within the central nervous system, diet-related metabolites have been linked to reduced neuroinflammation via modulation of microglial and astrocytic states. They have been linked to protection of mitochondrial function, maintenance of proteostasis, and preservation of blood-brain barrier (BBB) integrity. In AD and PD patients, adherence to this diet is associated with favorable changes in pathological hallmarks, including amyloid-beta (Aβ), tau, and α-synuclein accumulation. Nowadays, multi-omics tools, including single-cell transcriptomics, spatial transcriptomics and microbiome analysis, are widely used in this field, which helps researchers explore these complicated effects more deeply. Importantly, individual responses to the diet vary considerably due to differences in genetic background, gut microbial composition, and metabolic phenotypes, which underscore the need to move from generalized dietary guidelines toward personalized precision nutrition. The Mediterranean diet is not only a dietary pattern but also an effective way to modulate neuro-immune and metabolic networks. However, current evidence remains largely observational, and we critically discuss the need for more randomized controlled trials (RCTs) and standardized multi-omics data analysis frameworks. To sum up, the Mediterranean diet plays a neuroprotective role via the gut-immune-brain axis, and multi-omics techniques promote the development of precision nutrition. More trials and improved multi-omics systems are required to apply these research results in clinical practice.