Project description:A slower transmethylation of one-carbon substrates in the edematous form of severe acute malnutrition (ESAM) suggests that downstream aberrations in DNA methylation could drive differences in acute pathogenesis between ESAM and non-edematous malnutrition (NESAM). Here, we integrate genome-wide assessments of DNA methylation with corresponding gene expression profiles and sequence variation to show that relative to NESAM, acute ESAM is characterized by significant hypomethylation at 99% of differentially methylated loci in two SAM cohorts, whereas recovered adults show no significant differences in methylation. Hypomethylated loci correlate with both up- and down-regulation of proximal genes, which are associated with the clinical sub-phenotypes of kwashiorkor and enriched for GWAS hits linked to over-nutrition, including fatty liver and diabetes. Methylation at these loci also appears to be influenced by nearby genetic variation in a manner that varies with nutritional status. Our findings implicate epigenetic and genetic variation in ESAM pathophysiology and support methyl-group supplementation in ESAM management.
Project description:A high rate of early post-discharge mortality has been observed in children admitted with Severe Acute Malnutrition (SAM) in sub-Saharan Africa but the underlying causes and mechanisms are not well understood. We investigated whether there are biomarkers measured before discharge following medical stabilization and nutritional rehabilitation of children treated for SAM predict early post-discharge mortality and provide insights into causal mechanisms.
Project description:Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. To investigate the underlying mechanisms of hepatic dysfunction we used a rat model of malnutrition by placing weanling rats on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Low protein diet-fed rats developed hypoalbuminemia and severe hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated impaired peroxisomal function. Loss of peroxisomes was followed by accumulation of dysfunctional mitochondria and decreased hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial fatty acid β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. These findings provide important insight into the metabolic disturbances associated with malnutrition and have potentially profound clinical consequences with respect to the management of malnourished children worldwide.