title: Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis.
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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Rishu
authors.initials: R
authors.lastname: Dheer
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Santaolalla
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Davies
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Lang
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Phillips
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA.
authors.forename: Cristhine
authors.initials: C
authors.lastname: Pastorini
authors.affiliation: Department of Pathology, Palms West Hospital, Loxahatchee, Florida, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Vazquez-Pertejo
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida, USA Mabreu1@med.miami.edu.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D003092:Colitis / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D003106:Colon / Q000378:metabolism / Q000382:microbiology; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4