Quercetin and the gut-brain axis: Microbiome modulation, neuroprotection, and therapeutic implications

Quercetin is one of the dietary flavonols found mostlyin fruits and vegetables and is known to modulate the bidirectional communication among the gut microbiota, immune system, and central nervous system. Apart from its antioxidant and anti-inflammatory effects, it modulates gut microbial composition, the intestinal barrier, and neuroimmune pathways. Clinical translation is constrained because of low systemic bioavailability, extensive first-pass metabolism, and inter-individual variability caused by genetics and microbiome diversity. While nano delivery systems, phospholipid complexes, and metabolic co-administration have been proposed to improve absorption, the extent to which these interventions alter microbiota-mediated effects and yield measurable neurological outcomes in humans remains limited and requires further validation in well-controlled human studies. The evidence also supports a hormetic response, whereby moderate doses stimulate the body's adaptive defenses, whereas supra-physiological doses may have adverse effects. Therefore, researchers should focus on standardized human trials that include neurofunctional outcomes, cerebrospinal fluid biomarkers, and multi-omics approaches to clarify the associated mechanisms. In this review, we synthesize molecular, preclinical, and clinical evidence to advance a conceptual framework that elucidates the potential of this compound as a microbiota-modulating agent, principally on mechanistic and preclinical grounds, while clinical confirmation of its therapeutic efficacy in neuropsychiatric and neurodegenerative disorders remains limited. It emphasizes the significance of gut-level interactions and microbiota-derived metabolites rather than systemic bioavailability alone.