supports the survival of in a cystic fibrosis lung polymicrobial community through metabolic cross-feeding.

Cystic fibrosis (CF) is a multi-organ genetic disorder that affects more than 100,000 individuals worldwide. Chronic respiratory infections are among the hallmark complications associated with CF lung disease, and these infections are often due to polymicrobial communities that colonize the airways of persons with CF (pwCF). Such infections are a significant cause of morbidity and mortality, with studies indicating that pwCF who are co-infected with more than one organism experience more frequent pulmonary exacerbations, leading to a faster decline in lung function. Previous work established an CF-relevant polymicrobial community model composed of , , , and cannot survive in monoculture in this model. In this study, we leverage this model to investigate the interactions between and , allowing us to understand the mechanisms by which the two microbes interact to support the growth of specifically in the context of the polymicrobial community. We demonstrate a cross-feeding mechanism whereby metabolizes mucin into short-chain fatty acids that are, in turn, utilized by and converted into metabolites (succinate, acetate) that are cross-fed to , supporting its survival in the CF lung-relevant model. This work highlights the potential metabolic interactions among microbes in CF infections.IMPORTANCEPolymicrobial interactions impact disease outcomes in pwCF who suffer from chronic respiratory infections. Previous work established a CF-relevant polymicrobial community model that allows experimental probing of these microbial interactions to achieve a better understanding of the factors that govern the mechanisms by which CF lung microbes influence each other. In this study, we investigate the interaction between and , which are two highly prevalent and abundant CF lung microbes. We uncover a mechanism that involves complex cross-feeding between and to support the growth of the latter.