Exacerbation of murine ileitis by Toll-like receptor 4 mediated sensing of lipopolysaccharide from commensal Escherichia coli.
BACKGROUND
In the course of inflammatory bowel diseases (IBD) and acute murine ileitis following peroral Toxoplasma gondii infection, commensal Escherichia coli accumulate at inflamed mucosal sites and aggravate small intestinal immunopathology.


OBJECTIVE
To unravel the molecular mechanisms by which commensal E coli exacerbate ileitis.


METHODS
Ileitis was investigated in mice that lack Toll-like receptors (TLR) 2 or 4, specific for bacterial lipoproteins (LP) or lipopolysaccharide (LPS), respectively. Gnotobiotic mice, in which any cultivable gut bacteria were eradicated by antibiotic treatment, were used to study the role of LPS in ileitis.


RESULTS
Microbiological analyses revealed that E coli increase in the inflamed ileum. TLR4(-/-), but not TLR2(-/-), mice displayed reduced mortality and small intestinal immunopathology. Decreased interferon (IFN)-gamma and nitric oxide (NO) levels in the inflamed terminal ileum of TLR4(-/-) mice indicated that TLR4 signalling aggravates ileitis via local mediator release from immune cells. E coli strains isolated from the inflamed ileum activated cultured mouse macrophages and induced TLR4-dependent nuclear factor kappaB activation and NO production in human embryonic kidney 293 cells and in peritoneal macrophages, respectively. Most strikingly, in contrast with wild-type mice, gnotobiotic TLR4(-/-) mice were protected from induction of ileitis by treatment with purified E coli lipid A or colonisation with live E coli. Finally, prophylactic treatment with the LPS scavenger polymyxin B ameliorated T gondii-induced ileitis.


CONCLUSIONS
These findings highlight the innate immune system as a key player in T gondii-induced ileal immunopathology. Treatment with LPS or TLR4 antagonists may represent a novel strategy for prophylaxis and/or therapy of small intestinal inflammation in IBD.
Heimesaat
M M
MM
Institut für Mikrobiologie und Hygiene, Charité, Universitätsmedizin Berlin, Campus Charité Mitte, Dorotheenstr. 96,D-10117 Berlin, Germany.
Fischer
A
A
Jahn
H-K
HK
Niebergall
J
J
Freudenberg
M
M
Blaut
M
M
Liesenfeld
O
O
Schumann
R R
RR
Göbel
U B
UB
Bereswill
S
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D018988:Bacterial Translocation / Q000276:immunology; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D005856:Germ-Free Life; D007079:Ileitis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology; D007082:Ileum / Q000382:microbiology; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011112:Polymyxin B / Q000627:therapeutic use; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D011112:Polymyxin B