Epithelial-specific Toll-like Receptor (TLR)5 Activation Mediates Barrier Dysfunction in Experimental Ileitis

Area of Science:

• Gastroenterology
• Immunology
• Microbiology

Background:

• Toll-like receptor 5 (TLR5) and its ligand flagellin are implicated in Crohn's disease (CD).
• The precise mechanisms underlying TLR5's role in CD pathogenesis remain unclear.

Purpose of the Study:

• To investigate the role of flagellin/TLR5 signaling in a spontaneous mouse model of Crohn's disease-like ileitis (SAMP1/YitFc mice).

Main Methods:

• Assessed ileal Tlr5 expression and serum anti-flagellin antibodies in SAMP mice.
• Utilized bone marrow transplantation experiments to differentiate hematopoietic and non-hematopoietic contributions to TLR5 elevation.
• Examined ex vivo ileal tissue responses to TLR5 activation, including epithelial barrier resistance and tight junction protein expression.

Main Results:

• Ileal Tlr5 and anti-flagellin antibodies were elevated in SAMP mice, correlating with inflammation and dependent on the gut microbiome.
• Elevated ileal epithelial TLR5, independent of bone marrow origin, was observed in pre-inflamed SAMP mice.
• TLR5 activation ex vivo decreased ileal epithelial barrier resistance and altered tight junction protein expression.

Conclusions:

• Aberrant TLR5 expression in the ileal epithelium, augmented by the microbiome, contributes to impaired epithelial barrier function.
• TLR5 activation by flagellin compromises intestinal barrier integrity, suggesting a mechanism for chronic gut inflammation in experimental ileitis and potentially Crohn's disease.