Multi-omics study links kwashiorkor to tissue remodeling and lipid disruption

Kwashiorkor, the puzzling form of severe malnutrition marked by swelling of the feet, legs and sometimes the whole body, has defied a full molecular explanation for more than eighty years. Now a large multi-omics study conducted in rural Niger reports that children with the condition carry distinctive molecular signatures in their blood — a cluster of extracellular matrix proteins and a group of sphingolipids — that distinguish them from children with other forms of malnutrition and that shift toward normal levels as the children recover. The findings, published open access in the journal Biomarker Research, suggest that kwashiorkor is not simply a matter of missing nutrients but involves a systemic reorganization of tissue structure and lipid metabolism.

The study was conducted by researchers working with Epicentre and Médecins Sans Frontières, with collaborating laboratories in Belgium, and recruited 180 children aged 6 to 59 months in the Madarounfa Health District of the Maradi region between September 2018 and November 2019. The children were divided into three groups of 60 each: those with kwashiorkor, those with marasmus — severe wasting without edema — and non-acutely malnourished children. Crucially, the groups were matched by age, sex and a clinical triage score used as a proxy for illness severity, so that differences in blood chemistry could be attributed to the type of malnutrition rather than to how sick the children were overall.

To probe the biology of the disease, the investigators applied an unusually broad toolkit to blood, urine and stool samples: untargeted plasma lipidomics, metabolomics and proteomics, untargeted urine metabolomics, and 16S rRNA gene sequencing of the gut microbiome. The statistical design was deliberately strict. A molecular feature was considered specific to kwashiorkor only if it differed between children with kwashiorkor and the combined comparison groups, if it tracked with the severity of edema, and if it moved back toward normal after nutritional rehabilitation. Features that met only some of these criteria were not counted as candidate biomarkers.

The proteomic analysis produced the study’s clearest hit. Using factor analysis, the researchers condensed thousands of protein measurements into a smaller set of latent variables — statistically derived clusters of proteins that vary together. One such cluster, designated pLV7, contained the proteins lumican, gelsolin and tetranectin, all connected to the extracellular matrix, the fibrous scaffolding that supports tissues and blood vessels. This cluster was higher in children with kwashiorkor than in the other groups, rose with increasing edema severity, and fell significantly after treatment. Bootstrapping with 1,000 resampled datasets showed that the three-protein core was consistently recovered, with a mean Tucker congruence coefficient of 0.95 for the core, even though the full loading pattern was only modestly stable.

The lipidomic arm of the study told a complementary story. Of 21 lipid clusters extracted from the data, one — lLV5 — was lower in children with kwashiorkor, associated with edema severity, and increased after treatment. Its components were dominated by 17 mono- and di-unsaturated sphingomyelins, along with polyunsaturated cholesterol esters, a ganglioside, saturated hexosylceramides and several phosphatidylcholines. Sphingolipids are structural components of cell membranes and participate in cell signaling, proliferation and programmed cell death. Because circulating sphingolipids are synthesized mainly in the liver and intestine, the authors suggest that disturbances in these organs may contribute to the disease, although they caution that their data cannot confirm this hypothesis.

Not every omics layer yielded a signature. Neither the plasma metabolome nor the urine metabolome produced clusters that satisfied all three biomarker criteria, and the gut microbiome showed no significant differences among the three groups in diversity metrics or in differentially abundant taxa. The researchers acknowledge that the urine and microbiome analyses, based on only 88 and 38 children respectively, may have been underpowered, and that the microbiome comparison was intended as exploratory. The authors note that metabolomic findings have been inconsistent across studies in different countries, and suggest it is possible that the metabolome is more susceptible to geographic differences.

The network integration of the different data types added physiological context. The protein cluster pLV7 was negatively associated with total plasma protein and positively associated with blood sodium concentration, while the lipid cluster lLV5 tracked with total serum cholesterol. These connections matter because the extracellular matrix acts as a reservoir for sodium and helps maintain the integrity of blood vessels and lymphatic tissue. The authors propose that degradation of matrix proteins in vessel walls and lymphatic tissue could increase capillary permeability and impair interstitial fluid drainage, contributing to the edema that defines kwashiorkor. They frame this as a biologically plausible hypothesis rather than a demonstrated mechanism, noting that their proteomic method could not distinguish intact proteins from proteolytic fragments or identify the tissue of origin.

The study’s strengths lie in its matched design, its multi-omics breadth and its longitudinal element, with samples collected at recruitment, at hospital discharge and at the end of outpatient nutritional rehabilitation. Sensitivity analyses that removed children with positive malaria rapid tests, or that included only children with negative urine test strips, left the key associations intact. But the authors are candid about limitations. The study included only 60 children per group, offering an exploratory perspective; the triage score used for matching may not capture clinical severity in fine detail; children with marasmic kwashiorkor were not analyzed separately; and the results were not validated in an independent cohort. Field logistics, including remote training of staff who collected skin lesion data, may also have affected some measurements.

Conceptually, the findings push kwashiorkor research beyond the old dichotomy between protein deficiency and more multifactorial accounts involving oxidative stress, infection and the gut microbiome. The observed pattern — elevated circulating markers of matrix remodeling alongside depleted sphingolipids — is compatible with chronic inflammatory and oxidative injury, but the study was not designed to determine whether these processes are causes or consequences of the disease. The authors emphasize that their integration strategy cannot establish whether the two signatures represent independent processes, sequential events or parallel outcomes of a common upstream factor such as inflammation or overall illness severity.

For a condition that remains difficult to count even in population surveys, and that carries a higher reported mortality than marasmus in many settings, the identification of measurable molecular markers that track with disease severity and recovery is a practical step forward. For now, the study’s message is that the swollen child in a therapeutic feeding center in Niger carries in her blood the chemical traces of tissue under reconstruction — a systemic remodeling of the body’s structural scaffolding and its lipid signaling apparatus, rather than a simple shortage of food.

Subject of Research: Multi-omics biomarker study of kwashiorkor (edematous malnutrition) in children in Niger

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

Article References: Nackers, F., Polnay, K. D., Almey, R., Daled, S., Djibo, A. D., Saeger, S. D., Deforce, D., Dhaenens, M., Gansemans, Y., Glorieux, G., Guindo, O., Jenkins, B., Koulman, A., Lang, H.-J., Langendorf, C., Laukens, D., Mambula, C., Mukagatare, I., Parkington, D., … Gonzales, G. B. (2026). Multi-omics, multi-tissue analysis reveal role of extracellular matrix remodeling and sphingolipid homeostasis in edematous malnutrition (kwashiorkor). Biomarker Research, 14(1), Article 151. https://doi.org/10.1186/s40364-026-01016-9

Image Credits: AI Generated

DOI: 10.1186/s40364-026-01016-9

Keywords: kwashiorkor, edematous malnutrition, multi-omics, extracellular matrix, sphingolipids, proteomics, lipidomics, metabolomics, gut microbiome, Niger, severe acute malnutrition, biomarkers