Indole metabolites disrupt host mitochondrial energy production and inhibit Cryptosporidium parvum growth

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. Susceptibility declines with age likely due to changes in the microbiota and immune system. To explore microbial influences on susceptibility, we screened 85 microbiota- associated metabolites enriched in the adult gut for their effects on C. parvum growth in vitro. We identified eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B6 precursor, and indoles. Growth restriction of C. parvum by indoles does not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impaired host mitochondrial function and reduced total ATP, a key nutrient for the parasite. Consistent with diminished nutrient availability, administration of exogenous indoles delayed life cycle progression of the parasite in vitro. Additionally oral administration of indoles, or reconstitution of the gut microbiota with indole producing bacteria, reduced severity of infection when orally supplemented in mice. Collectively, these findings indicate that indole-producing microbiota provide resistance to Cryptosporidium infection by creating an inhospitable environment due to altered host energy metabolism.