Background: Environmental enteropathy (EE) contributes to growth failure in millions of children worldwide, but its relationship to clinical malnutrition has not been elucidated. We used RNA sequencing to compare duodenal biopsies from adults and children with EE, and from children with severe acute malnutrition (SAM), to define key features of these malnutrition-related enteropathies.

Methods: RNA was extracted and sequenced from biopsies of children with SAM in hospital (n=27), children with non-responsive stunting in the community (n=30), and adults living in the same community (n=37) using an identical sequencing and analysis pipeline. Two biopsies each were profiled and differentially expressed genes (DEGs) were computed from the comparisons of the three groups. DEG lists from these comparisons were then subjected to analysis with CompBio software to assemble a holistic view of the biological landscape and IPA software to interrogate canonical pathways.

Findings: Dysregulation was identified in goblet cell/mucin production and xenobiotic metabolism/detoxification for both cohorts of children, versus adults. Within the SAM cohort, substantially greater induction of immune response and barrier function, including NADPH oxidases was noted, concordant with broadly reduced expression of genes associated with the brush border and intestinal structure/transport/absorption. Interestingly, down regulation of genes associated with the hypothalamic-pituitary-adrenal axis was selectively observed within the cohort of children with stunting.

Interpretation: Gene expression profiles in environmental enteropathy and severe acute malnutrition have similarities, but SAM has several distinct transcriptional features. The intestinal capacity to metabolise drugs and toxins in malnourished children requires further study.

RNA sequencing was performed on biopsies of small intestinal mucosa in three groups of individuals in Lusaka, Zambia: adults with environmental enteropathy, children with stunting living in the same community as the adults, and children in hospital with severe acute malnutrition (SAM) and persistent diarrhoea. Data are FPKM values for individual transcripts obtained using RSEM software.

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