Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes...

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Toll-like receptor 4 (TLR4) plays a role in intestinal inflammation and microbiota recognition.
• Elevated epithelial TLR4 expression is linked to inflammatory bowel disease (IBD).
• The impact of heightened TLR4 signaling on intestinal homeostasis remains unclear.

Purpose of the Study:

• To investigate the effects of increased TLR4 signaling on intestinal epithelial function and microbiota composition.
• To utilize transgenic villin-TLR4 mice overexpressing TLR4 in the intestinal epithelium for this examination.

Main Methods:

• Generation and analysis of transgenic villin-TLR4 mice with epithelial overexpression of TLR4.
• Assessment of epithelial barrier function, antimicrobial peptide gene expression, and cell differentiation.
• Characterization of colonic luminal and mucosa-associated microbiota composition.
• Evaluation of colitis susceptibility in wild-type (WT) mice cohoused with villin-TLR4 mice and dextran sodium sulfate (DSS)-induced colitis models.

Main Results:

• Villin-TLR4 mice exhibited increased density of mucosa-associated bacteria and bacterial translocation.
• Heightened epithelial TLR4 signaling correlated with impaired epithelial barrier function, altered antimicrobial peptide expression, and modified epithelial cell differentiation.
• Significant differences in colonic microbiota composition were observed between villin-TLR4 and WT mice.
• WT mice cohoused with villin-TLR4 mice showed increased susceptibility to acute colitis.
• Microbiota alterations induced by epithelial TLR4 signaling were transmissible and exacerbated DSS-induced colitis.

Conclusions:

• Epithelial TLR4 expression significantly influences gut microbiota composition and the functional integrity of the intestinal epithelium.
• Increased epithelial TLR4 signaling leads to transmissible microbiota changes that enhance colitis susceptibility.
• Host innate immune signaling pathways, such as TLR4, can modulate the intestinal microbiome and impact host inflammatory responses.