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

Background Edematous malnutrition, aka kwashiorkor, is a phenotype of severe malnutrition whose pathophysiology remains poorly understood. Methods In this case-control study, we employed plasma lipidomics, metabolomics, and proteomics, urine metabolomics and gut microbiome profiling to delineate molecular features specific to kwashiorkor in 60 children aged 6–59 months from Niger compared to marasmus ( n = 60) and non-malnourished children (NAM) ( 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. Results We identified a plasma proteomic factor featuring lumican, gelsolin, and tetranectin and a lipidomic factor enriched in sphingolipids. Both differed in kwashiorkor compared to marasmus and NAM, were associated with edema grade, and trended towards normalcy after nutritional treatment, which are consistent with ECM remodeling and sphingolipid dysregulation. In contrast, neither (plasma and urine) metabolomic profiles nor gut microbiome composition showed kwashiorkor-specific signatures, although our urine and gut microbiome analyses may be underpowered. Conclusion These findings advance understanding of kwashiorkor pathophysiology beyond nutrient deficiency and highlight ECM and sphingolipid features associated with its distinct clinical and molecular characteristics compared to marasmus.