Gut Microbiome Dysbiosis Exacerbates Malaria Severity in Ugandan Children

Abstract

Malaria is a life-threatening infectious disease caused by the parasite Plasmodium. Sub-Saharan Africa faces the greatest disease burden and most deaths from severe malaria (SM) occur in children <5 years old. The pathogenesis of SM is not fully known, but murine studies implicate the gut microbiome. It remains unknown if gut microbiota contributes to SM pathogenesis in children. To address this knowledge gap, we sequenced the gut bacteria populations in stool samples from Ugandan children <5 years-old with SM and community children. Our analysis revealed that children with SM have gut bacteria dysbiosis, defined by an increased relative abundance of potentially pathogenic Enterobacteriaceae. Enterobacteriaceae thrive in the presence of inflammation and use diverse nutrients to support growth, and several features of SM associated with gut bacterial dysbiosis, including excess uric acid. Elevated blood uric acid levels during SM from hemolysis and impaired renal clearance likely increases levels of intestinal uric acid, which supports the growth of uricase producing bacteria such as Enterobacteriaceae. Furthermore, Enterobacteriaceae associated with multiple complications of SM such as coma, severe anemia, acidosis, acute kidney injury (AKI), and intestinal damage. Most positive blood cultures from children with SM grew Enterobacteriaceae. Moreover, increased Enterobacteriaceae abundance independently predicted post-discharge mortality in children with SM. The SM complication of excess intravascular hemolysis known as blackwater fever (BWF) also associates with post-discharge mortality, and its incidence has sharply increased in Eastern Uganda. In our cohort, 24% of children with SM reported BWF. This coincided with a significantly greater relative abundance of Enterobacteriaceae bacteria that can cause hemolysis. Our analysis identified 8% of stool samples from children with SM were positive for bacterial Shiga toxin genes, which may contribute to intravascular hemolysis through hemolytic uremic syndrome. This study identified gut dysbiosis during SM that associates with worse clinical complications and post-discharge mortality in a cohort of Ugandan children, suggesting that the gut microbiome may contribute to SM pathogenesis in humans.