Modelling the Gut-Bain Axis in Neurodegeneration: A Comprehensive Review of Organoids and Organ-on-Chip Systems

According to the World Health Organisation (WHO), conditions linked to the brain account for 28% of the social burden of all diseases, the largest sector, surpassing cancer and cardiovascular disease (CVD). Our incomplete understanding of human neurodegeneration biology is at the center of the devastating impacts it brings on our societies. A fundamental translational effect in those therapies is evident in that none have succeeded in registration-sized clinical trials. The outcome are coexisting therapies that remain largely palliative, managing symptoms or slowing decline but not providing hope for a reversal or cure. Increasing evidence has positioned the gut-brain axis (GBA) as a key modulator of neurodegeneration hallmarks, often inducing or progressing disorders such as Alzheimer’s, Parkinson’s and Multiple Sclerosis. Traditional research tools fail to recapitulate the accurate physiology of organ systems in humans, leading to the development of organoid technologies and organ-on-a-chip platforms. This literature review comprehensively analyses efforts to model neurodegenerative disorders through in vitro models, evaluating advancements in intestinal, cerebral, GBA, blood-brain barrier and other multi-organ systems. Further, the paper ties back to the known pathophysiology of such diseases and the GBA’s influence to evaluate limitations of current disease modelling approaches, offering future directions that enable applications in drug discovery. These technologies mark a transformative shift in methods to understand both the mechanistic causation and therapeutic strategies for previously incurable diseases, expanding the possibilities to improve the lives of millions of diagnosed patients.