Gut microbiome and plasma metabolic signatures of one-carbon metabolism differentiate oedematous and non-oedematous severe acute malnutrition

Childhood severe acute malnutrition (SAM) presents as non-oedematous (NO-SAM) or oedematous (O-SAM), with distinct outcomes but poorly understood mechanisms. We analyzed stool (metagenomic sequencing) and plasma (metabolomics) from 238 children with complicated SAM (79 NO-SAM, 159 O-SAM) and 141 adequately nourished controls (ANC) in Zimbabwe and Zambia, followed up to 48 weeks post-discharge. During hospitalization, O-SAM and NO-SAM showed significant microbiome differences; Lancefieldella parvula, a hydrogen-sulfide producer, was elevated in O-SAM. Metagenomics revealed enrichment of sulfur amino-acid and one-carbon metabolism pathways in O-SAM, consistent with plasma depletion of cysteine and homocysteine and higher histidine and phosphatidylcholines. Microbiome divergence persisted to 24 weeks, with delayed alpha diversity recovery in NO-SAM, while metabolomes remained distinct across groups for 48 weeks. These findings suggest microbiome-driven disruption of one-carbon metabolism in O-SAM and highlight persistent dysfunction during recovery, supporting microbiome-targeted interventions to improve long-term outcomes in complicated SAM.Five datasets are provided:HOPE-SAM_oedema_species_abundance_table.csv - Filtered and normalized species abundances for all stool metagenomes used in the study generated from MetaPhlAn4 output HOPE-SAM_oedema_pathway_abundance_table.csv - Filtered and normalized metagenome pathway abundances for all stool metagenomes used in the study generated from HUMAnN3 outputHOPE-SAM_oedema_species_abundance_ng.csv - Filtered and normalized species abundances for all nasogastric fluid metagenomes used in the study generated from MetaPhlAn4 output HOPE-SAM_oedema_metabolomics_dataset_table.csv - Metabolite abundances for all plasma metabolomes used in the study HOPE-SAM_oedema_metadata_zenodo_for_publication.xlsx - Metadata for all participants included in the study