Drug enteric metabolism in gut microbiota-brain crosstalk

Neurodegenerative diseases (NDs), such as Alzheimer's (AD) and Parkinson's disease (PD) represent the leading cause of illness and disability worldwide. In the effort to unveiling the etiopathogenesis of these neurological diseases, increasing attention has recently been paid to the emerging role of the gut microbiota (GMB) in the so-called gut-brain axis, and to the correlation of neurodegenerative processes with intestinal dysbiosis, either of genetic bases or induced by drugs and their metabolites. Over time, there has been a notable surge in the quantity of scientific publications pertaining to the gut-brain axis and GMB metabolism, reaching top levels in 2023-2025. As a result, the body of research on the effects of the gut-brain axis on AD and PD has begun to increase. Nonetheless, the identification of gut-derived metabolites and their effects on the central nervous system (CNS) is frequently missing or only partially reported. It is therefore necessary to raise awareness on the importance of enteric metabolism and its assessment while designing new drugs and investigating their pharmacokinetic properties, since both healthy and dysbiotic gut can hamper or modify drugs activity and efficacy. This review aims at providing a critical overview of gut-derived metabolism of different drugs, focusing on their effects on the GMB and gut-brain axis. The discussion focused on common therapeutic agents against AD and PD, as well as non-prescription drugs and food supplements with known beneficial effects on the CNS, reviewing relevant literature of the last decade.