Enteric Nervous System Dysfunction in Neurodegenerative Diseases

The enteric nervous system (ENS) comprises an extensive network of neurons and glia embedded within the gastrointestinal wall that governs motility, secretion and blood flow. In neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, ENS dysfunction often manifests as constipation, impaired transit and altered barrier integrity long before classical central nervous system symptoms emerge. Misfolded proteins, most notably α-synuclein, accumulate in enteric neurons and glial cells, triggering local inflammation, oxidative stress and microbial imbalance. Disruption of tight junction proteins compromises the intestinal epithelial barrier, permitting bacterial products to activate immune responses in the ENS and beyond. Via the gut–brain axis, pathogenic signals may ascend along vagal and sympathetic pathways to exacerbate central pathology, suggesting that early enteric changes contribute to disease progression. Preclinical models have revealed that interventions targeting neurotransmitter receptors, trophic factors or antioxidant pathways can restore both neuronal integrity and gut motility, highlighting the ENS as a promising therapeutic and diagnostic frontier in neurodegeneration.

Research from Nature Portfolio

Studies in toxin-based models of Parkinson’s disease have demonstrated that systemic neuroprotective agents can reverse enteric deficits. In the MPTP mouse model, oral administration of a copper–diaminetetraacetic acid complex restored populations of myenteric neurons and improved stool frequency, concomitant with reductions in glial reactivity and inflammatory markers in the colon. This work underscores a shared mechanism of neuronal vulnerability in gut and brain and validates enteric function as both a therapeutic endpoint and biomarker. In parallel, comparative analysis of five Parkinson’s models—including MPTP, 6-hydroxydopamine lesioning, oral rotenone exposure and α-synuclein transgenics—revealed model-dependent patterns of enteric neuron loss, nitrergic dysfunction and nuclear redistribution of neuronal markers. These alterations correlated closely with measures of gastrointestinal transit, emphasising that the choice of preclinical paradigm critically influences the nature and extent of ENS pathology and its relevance to human disease.

Enteric Nervous System Dysfunction in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in enteric nervous system dysfunction in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Enteric Nervous System: The intrinsic neural network controlling gastrointestinal motility, secretion and blood flow.

Enteric glial cells: Supporting cells within the ENS that regulate neuronal function, barrier integrity and immune responses.

α-Synuclein: A neuronal protein prone to misfolding and aggregation, central to synucleinopathies such as Parkinson’s disease.

Gut–brain axis: The bidirectional communication system linking the gastrointestinal tract and central nervous system via neural, hormonal and immune pathways.

Dysbiosis: An imbalance in the composition or function of the gut microbiota associated with disease states.

References

1. Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson’s disease. npj Parkinson's Disease (2023).
2. Ecklonia cava Polyphenols Have a Preventive Effect on Parkinson’s Disease through the Activation of the Nrf2-ARE Pathway. Nutrients (2024).
3. FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice CONTRIBUTIONS OF PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR (PRO-BDNF) AND MATURE BDNF*. Journal of Biological Chemistry (2016).
4. Constipation, deficit in colon contractions and alpha-synuclein inclusions within the colon precede motor abnormalities and neurodegeneration in the central nervous system in a mouse model of alpha-synucleinopathy. Translational Neurodegeneration (2019).
5. Enteric α-synuclein impairs intestinal epithelial barrier through caspase-1-inflammasome signaling in Parkinson’s disease before brain pathology. npj Parkinson's Disease (2022).
6. Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat. npj Parkinson's Disease (2018).
7. Enteric Glia at the Crossroads between Intestinal Immune System and Epithelial Barrier: Implications for Parkinson Disease. International Journal of Molecular Sciences (2020).
8. The association of enteric neuropathy with gut phenotypes in acute and progressive models of Parkinson’s disease. Scientific Reports (2021).
9. Changes in the sympathetic innervation of the gut in rotenone treated mice as possible early biomarker for Parkinson’s disease. Clinical Autonomic Research (2016).