This hypothesis/review proposes the endothelial surface layer–glycocalyx (ESL-GC) as a mechanistic interface linking gut microbiome dysbiosis, ion (especially K+) dysregulation and reactive gas nanobubbles to Parkinson's disease, reframing PD as an interface-based systems disorder rather than…

The paper presents a novel, testable conceptual framework that could point to new biomarkers and interventions (glycocalyx-targeting therapies, ion modulation, microbiome approaches) but is currently speculative and lacks direct experimental or clinical validation.

Parkinson's disease (PD) has generated extensive data without a unifying mechanism. Although growing evidence implicates the gut microbiome in PD pathogenesis, the gut-brain connection remains unresolved. While the nature of such interactions remains elusive, increasingly it is the glycocalyx, a nanoscale structural network lining endothelial surfaces that is emerging as a key linkage to disease mechanisms. We propose the endothelial surface layer-glycocalyx (ESL-GC) complex as the missing mechanistic interface. Within this framework, microbiome dysbiosis, disruption of ESL-GC structure and function, potassium dysregulation, other specific ion effects, and reactive gas nanobubbles act together as foundational contributors to PD pathology. This model reframes PD from a primarily dopamine-centred neurodegenerative disorder to an interface-based systems disorder and offers a coherent basis for integrating previously conflicting findings.