Intestinal Epithelial Cell-Derived LKB1 Suppresses Colitogenic Microbiota

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Intestinal epithelial barrier dysfunction is linked to dysbiosis.
• The role of intestinal epithelial cell (IEC)-derived factors in regulating gut microbiota remains incompletely understood.

Purpose of the Study:

• To investigate the novel role of liver kinase B1 (LKB1) in intestinal epithelial cells (IECs) in controlling colitogenic microbiota.
• To elucidate the mechanisms by which LKB1 influences susceptibility to colitis.

Main Methods:

• Generation of IEC-specific LKB1-deficient (LKB1^ΔIEC) mice.
• Induction of colitis using dextran sodium sulfate (DSS).
• Microbiota analysis and fecal microbiota transplantation.
• Measurement of IL-18 and antimicrobial peptide levels.

Main Results:

• IEC-specific deletion of LKB1 increased susceptibility to DSS-induced colitis.
• LKB1^ΔIEC mice exhibited a distinct shift in gut microbial composition, favoring colitogenic bacteria.
• Transfer of microbiota from LKB1^ΔIEC mice conferred colitis susceptibility to wild-type recipients.
• LKB1 deficiency reduced colonic IL-18 and antimicrobial peptide production.
• Exogenous IL-18 administration restored antimicrobial peptides, corrected microbial dysbiosis, and protected against DSS-induced colitis.

Conclusions:

• IEC-derived LKB1 plays a crucial role in suppressing colitogenic microbiota.
• LKB1 regulates the intestinal immune barrier through IL-18 production, thereby controlling gut microbial homeostasis.
• Targeting the LKB1-IL-18 axis may offer therapeutic strategies for colitis.