Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis.

Rishu Dheer,Julie M Davies,Rebeca Santaolalla,Maria T Vazquez-Pertejo,Jessica K Lang,Maria T Abreu,Matthew C Phillips,Cristhine Pastorini,V B Young

doi:10.1128/iai.01374-15

Rishu Dheer, Julie M Davies + Show 7 more

Open Access

https://doi.org/10.1128/iai.01374-15

Copy DOI

Abstract

Evidence obtained from gene knockout studies supports the role of Toll-like receptor 4 (TLR4) in intestinal inflammation and microbiota recognition. Increased epithelial TLR4 expression is observed in patients with inflammatory bowel disease. However, little is known of the effect of increased TLR4 signaling on intestinal homeostasis. Here, we examined the effect of increased TLR4 signaling on epithelial function and microbiota by using transgenic villin-TLR4 mice that overexpress TLR4 in the intestinal epithelium. Our results revealed that villin-TLR4 mice are characterized by increases in the density of mucosa-associated bacteria and bacterial translocation. Furthermore, increased epithelial TLR4 signaling was associated with an impaired epithelial barrier, altered expression of antimicrobial peptide genes, and altered epithelial cell differentiation. The composition of the colonic luminal and mucosa-associated microbiota differed between villin-TLR4 and wild-type (WT) littermates. Interestingly, WT mice cohoused with villin-TLR4 mice displayed greater susceptibility to acute colitis than singly housed WT mice did. The results of this study suggest that epithelial TLR4 expression shapes the microbiota and affects the functional properties of the epithelium. The changes in the microbiota induced by increased epithelial TLR4 signaling are transmissible and exacerbate dextran sodium sulfate-induced colitis. Together, our findings imply that host innate immune signaling can modulate intestinal bacteria and ultimately the host's susceptibility to colitis.

Highlights

Trillions of microbes coexist with mammalian cells in the gastrointestinal tract of the host in a relatively mutualistic environment [1, 2]
Because of the close proximity of the colonic microbiota to the intestinal epithelium and the critical role played by intestinal epithelial Toll-like receptor 4 (TLR4) in microbiota recognition and inflammation, the aim of our study was to determine the impact of intestinal epithelium-specific TLR4 signaling on microbial composition and the related host responses
We examined the quantity of the total bacteria in the intestinal mucosa and the lumen of villin-TLR4 and WT littermate mice by Real-time quantitative PCR (RT-qPCR) of the 16S rRNA operon

Summary

Introduction

Trillions of microbes coexist with mammalian cells in the gastrointestinal tract of the host in a relatively mutualistic environment [1, 2]. We have shown activation of the NF-␬B signaling pathway and increased expression of chemokines and proinflammatory genes at the baseline in the intestinal ECs (IECs) of villin-TLR4 mice [26] These findings established the double-edged sword of TLR4 function in the intestine, wherein both low and excessive TLR4 signaling can promote intestinal inflammation. Because of the close proximity of the colonic microbiota to the intestinal epithelium and the critical role played by intestinal epithelial TLR4 in microbiota recognition and inflammation, the aim of our study was to determine the impact of intestinal epithelium-specific TLR4 signaling on microbial composition and the related host responses. We show that TLR4 regulates the expression of antimicrobial genes by distinct mechanisms in different parts of the intestine To our knowledge, this is the first study to find that enhanced TLR4 signaling promotes colonic inflammation through dysbiotic microbiota

Objectives

Methods

Results

Conclusion