TLR4 deficiency reduces pulmonary resistance to <i>Streptococcus pneumoniae</i> in gut microbiota-disrupted mice

Streptococcus pneumoniae is a clinically important pathogen responsible for significant morbidity and mortality worldwide. Disruption of the host gut microbiota by antibiotics reduces the pulmonary resistance to S. pneumoniae. The aim of our study was to determine the potential role of TLR4 in the reduced pulmonary resistance to S. pneumoniae following gut microbiota disruption. Wild-type and TLR4-deficient mice were given broad-spectrum antibiotics for 3 weeks by oral gavage to disrupt the gut microbiota, and subsequently inoculated intra-nasally with S. pneumoniae. The extent of the decline in pulmonary resistance in both animal groups was evaluated in terms of the overall survival and pulmonary bacterial clearance. Both survival and pulmonary clearance of S. pneumoniae were lower in the TLR4-deficient mice with disrupted gut microbiota, compared to their intestinally healthy counterparts after pneumococcal infection. However, the degree of decline was much lower in the TLR4-deficient mice compared to the wild-type mice. Our findings indicate that impaired TLR4 function might be the basis of the reduced pulmonary resistance to S. pneumoniae caused by gut microbiota disruption.