Abstract The gut microbiome plays a critical role in the development of the immune system during the first year of life. Contact between immune cells and commensal microbes during early life helps to fine-tune this balance, and early-life perturbations to the microbiome have been linked to later susceptibility to a wide range of health issues, from gastrointestinal disorders such as irritable bowel syndrome or inflammatory bowel disease, to respiratory conditions including asthma and chronic obstructive pulmonary disease. The gut microbiome in premature infants has been well described to be significantly altered, with over-abundance of opportunistic Gram-negative Enterobacteriaceae. Premature infants are at higher risk for adverse outcomes to respiratory infections such as respiratory syncytial virus (RSV) due to their immunocompromised state and incomplete lung development. We hypothesize that the altered state of the premature microbiome affects the ability of the immune system to effectively deal with infection. Our preliminary data suggest that the altered gut microbiome in premature infants induces neutrophil-biased immune responses but weaker anti-viral interferon and antibody responses; the combination of both may contribute to more severe RSV-induced lung injury in premature infants and increase the risk of asthma in later life. This proposal aims to define the contributions of the altered gut microbiome to the outcome of RSV infection in preterm infants, and to identify metabolites that might be used to “normalize” the respiratory immune responses to RSV infection in premature infants and improve their lung functions.