title: Bacterial stimulation of the TLR-MyD88 pathway modulates the homeostatic expression of ileal Paneth cell α-defensins.
abstract: Paneth cell α-defensins are antimicrobial peptides involved in the control of the intestinal microbiota and immunological homeostasis. In mice, they are encoded by multiple, highly homologous genes (Defa). The transcriptional activity of ileal Defa genes was studied in response to pharmacological and genetic perturbations of the intestinal environment of C57BL/6 mice. Defa gene transcription was sensitive to oral antibiotic administration suggesting that commensal microbes regulate Defa expression. Ileal microbiota analysis showed that decreased transcription of Defa genes correlated with depletion of Lactobacillus. Defa expression was partially restored in vivo by lactobacillus administration to antibiotic-treated mice. Defa transcripts were less abundant in ex vivo, microbiota-free intestinal explants but recovered after explant exposure to UV-killed bacteria, Toll-like receptor (TLR)-2 or TLR4 agonists. Genetic deficiency of several TLRs or MyD88 led to dramatic drops in Defa transcription in vivo. These results show that Paneth cell Defa genes are regulated by commensal bacteria through TLR-MyD88 signaling and provide a further understanding of the dysregulation of intestinal homeostasis that occurs as a result of imbalances in the populations of commensal bacteria.
authors.affiliation: Michael Smith Laboratories, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Menendez
authors.forename: B P
authors.initials: BP
authors.lastname: Willing
authors.forename: M
authors.initials: M
authors.lastname: Montero
authors.forename: M
authors.initials: M
authors.lastname: Wlodarska
authors.forename: C C
authors.initials: CC
authors.lastname: So
authors.forename: G
authors.initials: G
authors.lastname: Bhinder
authors.forename: B A
authors.initials: BA
authors.lastname: Vallance
authors.forename: B B
authors.initials: BB
authors.lastname: Finlay
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment; D003106:Colon / Q000166:cytology / Q000382:microbiology; D006706:Homeostasis; D007778:Lactobacillus / Q000276:immunology; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D019879:Paneth Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011987:Receptors, Steroid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D053594:Myeloid Differentiation Factor 88; C490514:Nr2c2 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D023084:alpha-Defensins