Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa.
The gut microbiota is an environmental factor that determines renewal of the intestinal epithelium and remodeling of the intestinal mucosa. At present, it is not resolved if components of the gut microbiota can augment innate immune sensing in the intestinal epithelium via the up-regulation of Toll-like receptors (TLRs). Here, we report that colonization of germ-free (GF) Swiss Webster mice with a complex gut microbiota augments expression of TLR2. The microbiota-dependent up-regulation of components of the TLR2 signaling complex could be reversed by a 7 day broad-spectrum antibiotic treatment. TLR2 downstream signaling via the mitogen-activated protein kinase (ERK1/2) and protein-kinase B (AKT) induced by bacterial TLR2 agonists resulted in increased proliferation of the small intestinal epithelial cell line MODE-K. Mice that were colonized from birth with a normal gut microbiota (conventionally-raised; CONV-R) showed signs of increased small intestinal renewal and apoptosis compared with GF controls as indicated by elevated mRNA levels of the proliferation markers Ki67 and Cyclin D1, elevated transcripts of the apoptosis marker Caspase-3 and increased numbers of TUNEL-positive cells per intestinal villus structure. In accordance, TLR2-deficient mice showed reduced proliferation and reduced apoptosis. Our findings suggest that a tuned proliferation response of epithelial cells following microbial colonization could aid to protect the host from its microbial colonizers and increase intestinal surface area.
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Nives
N
Hörmann
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Inês
I
Brandão
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Sven
S
Jäckel
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Nelli
N
Ens
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Maren
M
Lillich
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Ulrich
U
Walter
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Junior Group Translational Research in Thrombosis and Hemostasis, Mainz, Germany.
Christoph
C
Reinhardt
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004926:Escherichia coli / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000382:microbiology; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D015854:Up-Regulation
D019394:Ki-67 Antigen; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3