Neuro-entero-cardiac bridge: could gut-derived catecholamine-loaded extracellular vesicles synchronize the pathogenesis of Parkinson’s disease, irritable bowel syndrome, and stress-triggered arrhythmias?
The gut–brain–heart axis is increasingly recognized as a clinically relevant interface in chronic and stress- responsive disorders. Parkinson’s disease (PD), irritable bowel syndrome (IBS), and stress-triggered arrhythmias show epidemiologic and mechanistic convergence through autonomic dysregulation, mucosal immune activation, barrier dysfunction, and systemic inflammatory signaling. However, the molecular messengers that could help “couple” these organ systems over time remain incompletely defined. Extracellular vesicles (EVs) represent a plausible integrative mechanism because they can transport regulatory cargo (RNAs, proteins, lipids) and influence distant tissues, including during inflammation and stress responses. We hypothesize that stress- responsive gut-linked EVs originating from intestinal epithelial, immune, enteroendocrine, and enteric neural compartments may contribute to shared vulnerability across PD, IBS, and arrhythmias by distributing inflammatory and neuroactive regulatory signals (especially microRNAs) systemically. Importantly, direct evidence that gut-derived EVs are “highly enriched” with catecholamines (dopamine, norepinephrine) in PD, IBS, or arrhythmia contexts is currently lacking; therefore, EV-mediated catecholamine transport is presented here as a testable sub-hypothesis rather than an established driver of pathology. Even if EV-associated catecholamines are detectable, they may constitute a minor fraction relative to synaptic/autonomic catecholamine signaling and could represent an epiphenomenon of stress biology rather than a dominant transport route. We outline falsifiable predictions and a rigorous experimental strategy that explicitly addresses EV heterogeneity, contamination by non-EV particles, and causality controls. If supported, gut-linked EV cargo profiles could provide biomarkers that stratify tri-system risk and point toward adjunctive therapeutic approaches that complement established gut–brain–heart pathways (vagus/autonomic signaling and microbiota-derived metabolites, including TMAO- related pathways)