ABSTRACT Recent studies in humans and mice have identified previously unknown interactions between the host gut microbiome and Plasmodium that dictate susceptibility to severe malaria. Yet, the specific members of gut microbiota and their functions responsible for differential malaria outcomes remain unknown. The objective of this application is to determine the gut bacteria function that shapes host immunity to Plasmodium and susceptibility to severe malaria. We have demonstrated that gut microbiota in mice affects the magnitude of parasite burden and severity of malaria by modulating Plasmodium-induced humoral immune responses in the spleen, the secondary lymphoid organ required for immune-mediated clearance of Plasmodium. Our data demonstrate that gut bacteria do not confer resistance to hyperparasitemia. Rather, specific bacteria confer susceptibility to hyperparasitemia. Specifically, gut Bacteroides species function within a microbial consortium to cause susceptibility to hyperparasitemia in mice. Of note, Ugandan children with severe malarial anemia have increased abundances of several Bacteroides species compared to children with asymptomatic Plasmodium falciparum infections. Importantly, colonizing hyperparasitemia-resistant mice with these human- associated Bacteroides species caused susceptibility to hyperparasitemia. These data strongly support the relevance and translational potential of our ongoing efforts using murine malaria to identify mechanisms by which gut bacteria cause susceptibility to severe malaria and investigate gut microbiome-based therapeutics to prevent severe malaria. Our data show that mice susceptible to hyperparasitemia have increased regulatory T cells (Tregs) in both intestinal tissue and the spleen before and during Plasmodium infection. Tregs have been shown in mice to inhibit humoral immunity to Plasmodium. Bacteroides are among the primary producers of the short-chain fatty acid (SCFA) propionate that induces Tregs. We have also published that mice susceptible to hyperparasitemia have increased amounts of propionate compared to hyperparasitemia-resistant mice. Intriguingly, we have published that treating hyperparasitemia-susceptible mice orally with the antibiotics metronidazole or vancomycin reduces the severity of malaria. Oral treatment with metronidazole decreases intestinal propionate levels, while oral treatment with vancomycin decreases colonic Tregs. These novel findings support the central hypothesis that propionate production by gut bacteria induces Tregs that dampen humoral immunity to Plasmodium, causing susceptibility to severe malaria. This hypothesis will be tested through the following aims: Aim 1. Determine if propionate-producing bacteria cause susceptibility to severe malaria by inducing Tregs that dampen humoral immunity. Aim 2. Determine if stool propionate levels and Tregs correlate with malaria disease severity in diverse groups of African children and mice.