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Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition
Allan Sheppard1, Sherry Ngo1, Xiaoling Li1
1The Liggins Institute, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand.
Insights
Epigenetic differences in skeletal muscle of adult survivors of severe acute malnutrition (SAM) suggest lasting developmental impacts. These findings in kwashiorkor and marasmus survivors highlight persistent, developmentally-induced phenomena affecting long-term health outcomes.
Area of Science:
- Developmental biology
- Epigenetics
- Nutritional science
Background:
- Severe acute malnutrition (SAM) presents as marasmus (wasting) or kwashiorkor (edema).
- Phenotypic differences between these forms may persist into adulthood.
- Developmental changes prior to SAM exposure might explain these persistent differences.
Purpose of the Study:
- To investigate if developmentally-induced epigenetic differences explain the distinct outcomes of kwashiorkor versus marasmus.
- To compare epigenetic profiles in adult survivors of these two forms of SAM.
Main Methods:
- Genomic DNA was extracted from muscle biopsies of adult survivors of kwashiorkor (n=21) and marasmus (n=23).
- Epigenetic profiles, specifically CpG methylation, were compared using the Infinium® 450K BeadChip array.
Main Results:
- Significant differences in CpG methylation were identified in 63 genes within skeletal muscle DNA.
- Differentially methylated genes were involved in immune function, body composition, metabolism, musculoskeletal growth, neuronal function, and cardiovascular pathways.
- These pathways align with the known pathophysiology differences in adult SAM survivors.
Conclusions:
- Findings suggest persistent developmental influences on adult physiology in SAM survivors.
- Epigenetic processes, potentially established before birth, may mediate infant responses to malnutrition and later-life consequences.
- This supports the predictive adaptive response model in human development.
Background:
Severe 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.
Methods:
We 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® 450K BeadChip array.
Findings:
We 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.
Interpretation:
These 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.
Funding:
Supported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge "Discover New Ways to Achieve Healthy Growth."
Evidence Before This Study:
Previous 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 Study:
This 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 Evidence:
These 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.
