Multi-omics, multi-tissue analysis reveal role of extracellular matrix remodeling and lipid transport dysfunction in edematous malnutrition (kwashiorkor)

Edematous malnutrition, aka kwashiorkor, is a phenotype of severe malnutrition whose pathophysiology remains poorly understood. In this case-control study, we employed plasma lipidomics, metabolomics, and proteomics, urine metabolomics and gut microbiome profiling to delineate molecular pathways specific to kwashiorkor in 60 children aged 6–59 months from Niger compared to marasmus (n = 60) and non-malnourished children (n = 60) matched by age, sex, and clinical triage score. Features were defined as kwashiorkor-specific if they also correlated with edema severity and normalized following nutritional rehabilitation. Our analyses revealed that kwashiorkor is marked by increased extracellular matrix (ECM) degradation, evidenced by elevated plasma ECM proteins, and by disrupted sphingolipid homeostasis. Neither plasma nor urine metabolomic profiles, nor gut microbiome signatures, showed unique alterations associated with kwashiorkor. These findings suggest that kwashiorkor may be a combination of nutritional deficiencies and the disruption of the ECM and sphingolipid metabolism, potentially linked with an inflammatory syndrome.