# Beyond Organ Boundaries: Molecular Mechanisms of Hepatic Encephalopathy and Parkinson’s Disease from the Perspective of the Gut–Liver–Brain Axis

## TL;DR

This paper explores how liver dysfunction can lead to neurological issues like Parkinson’s disease through the gut–liver–brain axis.

## Contribution

It introduces a novel hypothesis that hepatic encephalopathy creates a neurotoxic environment that may trigger or worsen Parkinson’s disease.

## Key findings

- Ammonia toxicity and neuroinflammation from liver disease may promote α-synuclein aggregation linked to Parkinson’s disease.
- Liver dysfunction can alter gut microbiota and neurotransmitter balance, contributing to Parkinson’s-like pathology.
- The study suggests that targeting the gut–liver–brain axis could lead to new therapies for both conditions.

## Abstract

Hepatic encephalopathy (HE), a severe neurological complication of liver dysfunction, has long been regarded as a clinical issue confined to liver disease. However, recent clinical observations and basic research have revealed complex pathophysiological connections between HE and Parkinson’s disease (PD), 2 seemingly independent conditions. Patients with HE often exhibit irreversible extrapyramidal symptoms that closely resemble the motor disorders of PD; meanwhile, epidemiological studies suggest that individuals with liver disease—particularly non-alcoholic fatty liver disease (NAFLD)—may face an increased risk of developing PD. From the perspective of the gut–liver–brain axis, this study systematically explores the molecular mechanisms linking HE and PD, proposing a core hypothesis: HE creates a unique “neurotoxic soil” through ammonia toxicity, systemic neuroinflammation, and gut–liver–brain axis dysfunction. This soil may trigger PD in susceptible individuals, accelerate subclinical PD progression, or mimic PD-like pathology. The study analyzes in depth the direct regulatory role of ammonia in α-synuclein (α-syn) aggregation, the impact of liver disease-driven neuroinflammation on microglial activation and α-syn propagation, and the hypothesis of liver-derived α-syn transmission via the gut–liver–brain axis. It further discusses synergistic mechanisms such as manganese deposition, neurotransmitter imbalance, and gut microbiota metabolites. Based on these mechanisms, the study prospects translational medical applications, including the development of diagnostic biomarkers and novel therapeutic strategies such as “ammonia clearance plus” and gut–liver–brain axis targeting. This work provides new insights into how environmental metabolic factors contribute to neurodegenerative diseases and offers a theoretical basis for the combined prevention and treatment of HE and PD.