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Vagal stimulation ameliorates murine colitis by regulating SUMOylation
Ayman Youssef1,2, Ata Ur Rehman1, Mohamed Elebasy1
1Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Science Translational Medicine
|November 20, 2024
Summary
Decreased vagal nerve activity worsens inflammatory bowel disease (IBD). Stimulating the vagus nerve inhibits SUMOylation, a key process in IBD, offering a new therapeutic target for this chronic condition.
Area of Science:
- Gastroenterology
- Neuroimmunology
- Molecular Biology
Background:
- Inflammatory bowel diseases (IBDs) are chronic, incurable conditions affecting millions globally.
- The exact causes of IBD remain unknown, contributing to reduced lifespan and quality of life.
Purpose of the Study:
- To investigate the role of autonomic parasympathetic tone in IBD pathogenesis.
- To explore vagal nerve stimulation as a therapeutic strategy for IBD by targeting SUMOylation.
Main Methods:
- Utilized mouse models of IBD to study the effects of decreased and stimulated parasympathetic tone.
- Analyzed colonic biopsies from patients and mice for SUMOylation markers.
- Employed genetic knockout models (Sumo1, Sumo3) and bone marrow transplantation.
- Tested the efficacy of vagal nerve stimulation and a SUMO-activating enzyme inhibitor (TAK-981).
Main Results:
- Reduced parasympathetic tone increased IBD susceptibility and mortality in mice.
- Vagal stimulation ameliorated colitis by inhibiting SUMOylation, independent of the IL-10/cholinergic pathway.
- SUMO2 and SUMO3 were elevated in active IBD.
- Sumo3 deletion protected against colitis; Sumo1 deletion halted its progression.
- TAK-981 treatment improved IBD models, reduced intestinal permeability, and bacterial translocation.
Conclusions:
- Vagal neuromodulation inhibits SUMOylation, reprogramming stress responses and ameliorating IBD.
- SUMOylation presents a novel therapeutic target for inflammatory bowel diseases.
