Background: Alzheimer's, Parkinson's, and Huntington's are neurodegenerative conditions that are progressive in nature, with neuronal degeneration and toxic protein buildup. Although the brain has been the focus of most studies, recent research has highlighted the gutbrain axis, which is considered to play a significant role in disease processes. The autophagylysosomal pathway (ALP), as a major system of cellular waste clearance, has emerged as a possible mediator of this cross-talk. In the case of ALP impairment, gut-brain communication can be disrupted, and inflammation may be promoted. Method: This review examines the role of ALP dysfunction and gut-brain interaction and how it may contribute to the progression of major neurodegenerative diseases. It also outlines therapeutic approaches currently being studied, aimed at restoring ALP functionality. Databases such as PubMed, Scopus, and Google Scholar were searched to identify relevant studies published within the past decade. Both preclinical and clinical research were considered, with a focus on mechanistic information about ALP-gut-brain interactions. Results: Preclinical evidence indicates that ALP impairment disrupts gut barrier function, the microbiota community, and systemic inflammatory pathways, which may spread to the brain and promote protein aggregation and neurodegeneration. Discussion: These processes involve genes such as GBA, LRRK2, and mTOR. Probiotics, fecal microbiota transplantation (FMT), and pharmacological inducers of autophagy have been shown to have positive effects in experimental models, but the clinical evidence is limited, inconclusive, heterogeneous, and insufficient. Conclusion: Gastrointestinal homeostasis and neurodegeneration are mechanistic relationships that impair ALP. Nevertheless, although this route presents a promising option for clinical modulation in clinical experiments, its extrapolation to the effective treatment of humans is questionable and must be tested through a stringent clinical trial.
Prajapati et al. (Tue,) studied this question.