Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition

Abstract

BackgroundSevere acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences.MethodsWe extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n = 21) or marasmus (n = 23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450 K BeadChip array.FindingsWe found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM.InterpretationThese findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences.FundingSupported by a Grant from the , Grand Challenge “Discover New Ways to Achieve Healthy Growth.”Evidence Before This StudyPrevious research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood.Added Value of This StudyThis study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences.Implications of All the Available EvidenceThese data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.

Edematous severe acute malnutrition is characterized by hypomethylation of DNA

“…We deliberately focused on differences incurred in the context of acute starvation, such that the molecular changes described are specific to the acute pathology of ESAM, and relative to NESAM. This differentiates our study from previous studies of more general malnutrition that are agnostic to the form of SAM 29,30 . Similarly, by integrating molecular correlates of expression and assessing the contribution of cis- acting genetic variation, we provide a unique view of this gene-environment response that may hold lessons for other disorders.…”

“…Genes implicated in our ESAM study showed little-to-no overlap with those noted in a previous study of methylation in adult survivors of malnutrition 29 ; however, that study did not include the severity or type of SAM, and primarily focused on whole blood samples, making direct comparisons difficult. Nonetheless, it may be that the underlying mechanisms postulated here are still relevant—mitotic turnover among growing children is typically higher than in adults; and, whereas buccal epithelium is dynamically replenished, other cell types demonstrate less continuous renewal, allowing aberrations in methylation incurred during childhood to be perpetuated in tissues such as heart or muscle, potentially leading to the long-term health consequences that have been associated with the divergent SAM phenotypes 30,69,70 .…”

“…These differences in 1-carbon metabolism between ESAM and NESAM, however, are not observed after recovery from SAM, implying that nutritional and dietary recovery involves a reversal of the biochemical changes observed during the acute illness. While previous studies have shown altered DNA methylation in individuals with a history of severe acute malnutrition more generally 29,30 , none compared DNA methylation between the edematous and nonedematous forms of SAM, particularly during acute disease. Since the phenotypic differences that characterize the two forms of SAM are only evident during acute malnutrition, concomitant molecular changes incurred during acute illness could potentially highlight important drivers of the differing pathophysiologies.…”

Evolutionary and developmental mismatches are consequences of adaptive developmental plasticity in humans and have implications for later disease risk

“…Epigenetic analysis of skeletal muscle biopsies identified significant differences in methylation over 133 CpG loci. These loci included genes implicated in glucose metabolism, body size and body composition [68], lending biological plausibility to the findings.…”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…A general trend towards reduced promoter methylation levels of genes involved in energy metabolism, myogenesis, contractile activity, and oxidative stress resistance became apparent when global methylation patterns in skeletal muscle of healthy aged men with a lifelong history of physical activity were compared to “couch potatoes” of the same age group (Sailani et al, 2019). Reciprocally, also “bad memories” inflicted by physical inactivity, unhealthy diet, and prenatal stress have been reported to become reflected by differential DNA methylation patterns in skeletal muscle tissue (Alibegovic et al, 2009; Jacobsen et al, 2012; Jacobsen et al, 2014; Nilsson & Ling, 2017; Nitert et al, 2012; Sharples, Polydorou et al, 2016; Sheppard et al, 2017).…”