Gut Microbiota Composition Is Associated with Severity of Disease in Patients with <i>P. Falciparum</i> Malaria

Background: In severe Plasmodium falciparum malaria, mature blood-stage parasites sequester in the intestinal microvasculature and compromise gut barrier integrity, with subsequent translocation of Gram-negative bacteria and bacterial products into the circulation. The role of the gut microbiota in the pathogenesis of life-threatening complications of severe malaria, such as acidosis or concomitant sepsis, is unknown.Methods: A prospective observational study was conducted to profile the gut microbiota composition of adult patients with severe and uncomplicated falciparum malaria and healthy volunteers in Bangladesh, by sequencing the V4 region of the 16S rRNA gene PCR-amplified from faecal DNA. Plasma markers of P. falciparum parasite biomass and gut barrier integrity were measured to determine the relationship between the gut microbiota and severity of disease. Findings: Patients with high parasite biomass had reduced gut integrity and increased levels of gut-derived D-lactate in their blood. The gut microbiota of patients with severe malaria was significantly enriched with potentially pathogenic Enteroccocus and Escherichia/Shigella species. Plasma D-lactate levels were associated with the abundance of known lactate-producing species in the gut microbiota.Interpretation: This first report of the gut microbiota in patients with severe malaria shows a pathogenic host-parasite-microbe interaction, and highlights the gut microbiota as a target for adjunctive therapies.Trial Registration: The trial was registered at ClinicalTrials.gov [NCT02451904].Funding Statement: This work was supported by the Wellcome Trust [106698/B14/Z], a Nuffield Department of Medicine Prize Scholarship (SJL), the Netherlands Organization for Scientifc Research (VIDI-grant to WJW and Spinoza Award and SIAM Gravitation - grant 024.002.002 to WMdV).Declaration of Interests: The authors declare no competing interests.Ethical Approval Statement: This was a sub-study of an observational study protocol that was reviewed and approved by the local ethics review board, the Chittagong Medical College Ethics Committee, Bangladesh, and the Oxford Tropical Research Ethics Committee (OxTREC), in the United Kingdom.