Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

Area of Science:

• Genomics
• Pediatric Nutrition
• Gastroenterology

Background:

• Environmental enteric dysfunction (EED) impedes childhood growth and survival, impacting Sustainable Development Goals.
• Understanding EED's molecular mechanisms is crucial for developing effective interventions.

Purpose of the Study:

• To investigate the duodenal methylome and transcriptome in children with EED.
• To identify biomarkers associated with growth faltering in EED.
• To differentiate EED's molecular signatures from celiac disease.

Main Methods:

• Longitudinal study (SEEM) of 416 children from birth to 24 months in Pakistan.
• Biomarker analysis at 9 months, growth assessment at 24 months.
• Duodenal methylome and transcriptome analysis in undernourished children and controls.

Main Results:

• Insulin-like growth factor-1 (IGF-1) and ferritin predicted linear growth; leptin predicted weight gain.
• EED transcriptome showed suppressed antioxidant/metabolism genes and induced immune response genes.
• EED-specific epigenetic changes included hyper-methylation of metabolism/barrier genes and hypo-methylation of immune/proliferation genes.

Conclusions:

• Reduced IGF-1 is linked to stunting; leptin and immune/lipid metabolism gene signatures are implicated in wasting.
• These findings suggest novel therapeutic targets for EED unresponsive to nutrition.
• ClinicalTrials.gov identifier: NCT03588013.