The human brain has traditionally been considered an isolated organ until the establishment of the microbiome-gut-brain axis (MGBA) overturned that concept. Based on recent reports, the present review provides confirmatory evidence that there is a complex communication in the MGBA that links the central nervous system with the resident microbial community of the gastrointestinal tract. A complex, highly sophisticated molecular dialogue involving immune and neuroinflammatory molecules, signaling via the vagus nerve and neural pathways, and key metabolic and endocrine routes facilitates cross-talk between the brain and the gut microbiome. Crucial microbial metabolites, such as bile acids and short-chain fatty acids (SCFAs), neurotransmitter release, and modulation of systemic inflammation are highlighted as primary mediators of gut-brain interactions. In recent times, research has shifted from establishing associations to elucidating precise mechanisms between brain physiology and the composition of the gut microbial community. Recent studies have emphasized linking specific bacterial taxa to neurological outcomes in Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD). Emerging therapeutic modalities such as engineered live biotherapeutics, next-generation psychobiotics, precision nutrition, and fecal microbiota transplantation are promising avenues for next-generation neurotherapeutics. However, the path to clinical translation is fraught with challenges, including methodological heterogeneity and reproducibility, establishing causality, and confounding host factors. This review concludes with a forward-looking roadmap that emphasizes multi-omics integration, standardization, human-relevant disease models, and personalized therapeutic strategies to decode the MGBA and exploit its full potential, which could revolutionize the treatment of brain disorders.
