Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria

Malaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.


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Sex-based analyses was performed in human subjects and not shown to effect malaria outcomes.

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Healthy community children that were P. falciparum microscopy negative were classified as Pf Neg, while community children that were P. falciparum microscopy positive were classified as Pf pos.
Severe malarial anemia was defined as P. falciparum smear or RDT positive and serum hemoglobin level ! 5 g/dL.
Children between the ages of 0.5 to 4 years old, with 5 most common clinical manifestations of severe malaria (cerebral malaria, CM; respiratory distress, RD; severe malarial anemia, SMA; malaria with complicated seizures, M/S; and prostration) were enrolled in a prospective longitudinal cohort study at two sites: 1) the Pediatric Acute Care Unit at Mulago National Referral Hospital in Kampala, Uganda, and 2) the Pediatric Emergency Ward at the Jinja Regional Referral Hospital in Jinja, Uganda.Children from the same neighborhoods without active illness or fever at time of enrollment were enrolled in the healthy community control group.
Ethics approval and consent to participate Written informed consent was obtained from the parents or legal guardians of all study participants.Sample for mouse studies were calculated with five mice/group based on experience with a range of experimental designs and readouts studying murine malaria and the gut microbiome that yields >80% power when alpha equals 0.05 to identify as little as 1.6-fold differences with standard deviations ranging 20-40% of the group means.
No data were excluded Mouse experiments have been replicated at least twice.Analysis of stool bacteria community analysis has not been replicated.
Children were assigned to respective groups based on clinical definitions of those groups.
Investigators were not blinded owing to the need treat different groups of mice, and monitor outcomes and the nature of the clinical observation study.

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About 5 ul ul whole blood was collected from a tail snip in in 100 ul ul cold 1X 1X PBS.Whole blood was fixed in in 0.00625% glutaraldehyde, stained with conjugated antibodies, and ran immediately on on a flow cytometer.Attune Next (Invitrogen) and BD BD LSRFortessa (BD Bioscience) Ethical approval was granted by the Institutional Review Boards at Makerere University School of Medicine (Ref: 2013-141, date approved: September 23, 2014), the University of Minnesota (Ref: 1309M42501, date approved: September 23, 2013) and subsequently moved to Indiana University (Ref: 1412213778, date approved: January 20, 2015).The Uganda National Council for Science and Technology approved the study (Ref: HS1522, date approved: May 12, 2013) Stool sample size was determined based on the number of available stool samples from children in the different categories at time of study initiation.