The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection

Area of Science:

• Microbiology
• Neuroscience
• Immunology

Background:

• Clostridioides difficile infection (CDI) is a significant cause of hospital-acquired infections.
• Severe CDI is characterized by hyperactivation of the host immune response.
• The role of the sympathetic nervous system (SNS) in CDI pathogenesis is not well understood.

Purpose of the Study:

• To investigate the impact of the sympathetic nervous system (SNS) on the severity of Clostridioides difficile infection (CDI).

Main Methods:

• Utilized mouse models of CDI.
• Administered inhibitors of SNS activity, including chemical sympathectomy and norepinephrine synthesis inhibitors.
• Investigated the effects of alpha 2 adrenergic receptor blockade and genetic ablation.

Main Results:

• Inhibition of SNS activity significantly reduced mortality and disease severity in CDI mouse models.
• Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorated intestinal inflammation, disease severity, and mortality.
• Norepinephrine synthesis inhibition also decreased mortality and disease severity.

Conclusions:

• The sympathetic nervous system (SNS) plays a critical role in exacerbating Clostridioides difficile infection (CDI) severity.
• The alpha 2 adrenergic receptor is implicated in CDI pathogenesis.
• Targeting neural pathways, specifically the SNS and alpha 2 adrenergic receptor, may offer novel therapeutic strategies for severe CDI.