Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Area of Science:

• Immunology
• Gastroenterology
• Microbiology

Background:

• The intestinal epithelium forms a critical barrier between the gut microbiota and the bloodstream.
• Sepsis is associated with impaired intestinal barrier function, exacerbating systemic inflammation.
• Cathelicidin (Cnlp) expression is altered in sepsis, but its role in intestinal barrier dysfunction remains unclear.

Purpose of the Study:

• To investigate the role of cathelicidin (Cnlp) in polymicrobial sepsis-induced intestinal barrier dysfunction.
• To evaluate the therapeutic potential of vitamin D3 in a murine model of polymicrobial sepsis.

Main Methods:

• Cecal-ligation and puncture (CLP) model in wild-type and Cnlp knockout mice.
• Assessment of mortality, sepsis scores, ileal histology, biochemistry, immunology, and transcriptomics.
• Evaluation of prophylactic and therapeutic administration of vitamin D3 (cholecalciferol and 1alpha, 25-dihydroxyvitamin D3).

Main Results:

• Cnlp knockout mice exhibited increased mortality, sepsis severity, intestinal permeability, and bacterial load post-CLP.
• Cnlp deficiency led to goblet cell loss, increased apoptosis, and altered immune cell infiltration (M1 macrophages, neutrophils).
• Treatment with 1alpha, 25-dihydroxyvitamin D3 reduced mortality and sepsis severity, while cholecalciferol administration worsened outcomes.

Conclusions:

• Endogenous cathelicidin (Cnlp) is essential for preserving intestinal barrier integrity during polymicrobial sepsis.
• Cnlp modulates immune cell infiltration, contributing to barrier defense.
• 1alpha, 25-dihydroxyvitamin D3 shows therapeutic potential for sepsis, whereas cholecalciferol may be detrimental.