Microbiota produced indole metabolites disrupt host cell mitochondrial energy production and inhibitCryptosporidium parvumgrowth

Abstract

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. Susceptibility rapidly declines with age, associated with changes in the microbiota. To explore microbial influences on susceptibility, we screened 85 microbiota- associated metabolites enriched in the adult gut for their effects onC. parvumgrowth in vitro. We identified eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B6precursor, and indoles. Growth restriction ofC. parvumby indoles did not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impaired host mitochondrial function and reduced total cellular ATP, as well as directly reduced the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole producing bacteria, delayed life cycle progression of the parasite in vitro and reduced severity ofC. parvuminfection in mice. Collectively, these findings indicate that microbiota metabolites contribute to colonization resistance toCryptosporidiuminfection.