Gut flora enhance bacterial clearance in lung through toll-like receptors 4

Background: The influence of the gut flora on lung inflammatory reaction against bacterial challenge remains undefined. This study was designed to investigate whether gut flora enhances lung defense against E. coli pneumonia through TLR4 signaling. Methods: C3H/HeN (WT) mice and C3H/HeJ (TLR4 deficient) mice were treated with antibiotics in drinking water for 4 weeks to deplete gut commensal microflora. At week 3, drinking water was supplemented with lipopolysaccharide (LPS); a ligand for TLR4, to trigger TLRs in intestinal tract. At the end of 4th week, E. coli was injected to trachea to induce E. coli pneumonia. Results: We found that commensal depletion by antibiotic pretreatment before E. coli pneumonia challenge induced a 30% decrease of MPO activity in the lung, a significant decrease of bacterial killing activity of alveolar macrophage, and bacterial counts in C3H/HeN mice but not in C3H/HeJ (TLR4 deficient) mice. LPS, a TLR4 ligand, supplementation during antibiotic pretreatment reversed these effects and decreased E. coli pneumonia-induced mortality in C3H/HeN mice. Furthermore, commensal depletion induced a suppression of NF-kappa B DNA binding activity and an increase of KC, MIP-2, IL-1b expression in the lung in C3H/HeN mice but not in C3H/HeJ mice. Conclusions: Taken together with that commensal depletion increased E. coli pneumonia-induced mortality and LPS supplementation decreased it, we conclude that gut flora enhances bacterial clearance against E. coli pneumonia through TLR4.