Thrombin mediates vagal apoptosis and dysfunction in inflammatory bowel disease

Area of Science:

• Neuroscience
• Gastroenterology
• Immunology

Background:

• Inflammatory bowel disease (IBD) is linked to autonomic dysfunction, affecting gastrointestinal function and patient well-being.
• The dorsal motor nucleus of the vagus (DMV) in the brainstem houses efferent vagal neurons crucial for parasympathetic gut innervation.
• Understanding IBD's impact on DMV neurons is vital for addressing associated morbidity.

Purpose of the Study:

• To investigate the effects of IBD on the survival and function of neurons within the dorsal motor nucleus of the vagus (DMV).
• To characterize the role of glial activation and prothrombin/thrombin signaling in the DMV during IBD.

Main Methods:

• Colitis was induced in rats using TNBS (trinitrobenzenesulfonic acid) enema.
• Neuronal apoptosis and glial activation in the DMV were assessed using TUNEL labeling and immunofluorescence.
• Prothrombin production was quantified, and thrombin's effects on DMV neurons were studied in vivo and in primary cultures.

Main Results:

• TNBS-induced colitis significantly increased DMV neuronal apoptosis (12.7%) and caspase-3 activation.
• Glial cells (astrocytes and microglia) in the DMV showed increased activation, with prothrombin closely associated with microglia.
• Direct thrombin administration to the DMV induced apoptosis and impaired neuronal calcium signaling, effects blocked by a PAR-1 antagonist.

Conclusions:

• IBD is associated with DMV microglial activation and increased prothrombin production.
• Thrombin within the DMV induces vagal neuron apoptosis and reduces neuronal sensitivity to neurotransmitters.
• These findings highlight a novel mechanism of autonomic dysfunction in IBD impacting gut-brain communication.