Abstract While functions of the gastrointestinal (GI) microbiome include maintenance of immune homeostasis and protection against infectious disease, its role in determining disease severity during Plasmodium infection has been limited to mouse models and observational human cohorts. Here, we performed controlled Plasmodium infection in both humans and rhesus macaques (RMs) to experimentally determine the impact of GI microbiome composition on disease progression. Through analysis of serially collected microbiome samples, we identified a high-risk microbial signature that strongly associated with increased risk of developing severe parasitemia in human participants. Importantly, we identified a parallel phenomenon in RMs. The combined weight of this evidence demonstrates that pre-infection GI microbiome composition is highly indicative of P. falciparum disease risk. Moreover, our observation that P. fragile -microbiome dynamics in RMs closely mirrors P. falciparum -microbiome interactions in humans strongly supports the use of this model in pre-clinical investigations of novel microbiome-targeting approaches to reduce malaria burden.

High-risk microbial signatures are associated with severe parasitemia in controlledPlasmodiuminfections of both humans and rhesus macaques