Application of mucosal functional genomics to childhood undernutrition and stunting: Insights into mechanisms and targeted interventions

Abstract

Despite extensive global health efforts, maternal and child undernutrition continue to account for substantial morbidity and mortality in low-income and middle-income countries [1]. This includes a high rate of mortality for children hospitalized with severe acute malnutrition (SAM), and lasting effects upon cognition in those with chronic undernutrition and stunting. Efforts focused upon improved nutrition and sanitation early in life have yielded only partial benefits, suggesting a critical knowledge gap in our understanding of underlying mechanisms [1]. This may include a common environmental enteric dysfunction (EED) underlying both acute and chronic forms of malnutrition [2]. While histopathologic features of EED were recognized as early as the 1960s, a comprehensive multi-omic approach using mucosal samples obtained during endoscopy has only recently been applied [2]. It was hypothesized that specific microbial shifts, and associated mucosal epigenetic, transcriptomic, and proteomic features, would be associated with refractory undernutrition. In the August 2021 issue of EBioMedicine, Kelly et al [3] tested for duodenal transcriptomic variation in an elegant design which included both children and adults with EED and stunting living in the same disadvantaged community in Zambia, and hospitalized children with SAM. This allowed the investigators to test for common and distinct features of childhood EED with stunting and SAM. Histopathologic analysis confirmed core features of EED including villous blunting, paneth and goblet cell depletion, and an increase in intra-epithelial and lamina propria lymphocytes in both groups. Participants with a treatable fecal pathogen were excluded, supporting a likely role for the commensal microbial community in driving inflammatory responses. Core transcriptomic features of EED identified in both groups of children, relative to adults living in the same community, implicated dysregulated mucin production and xenobiotic metabolism/ detoxification. In addition, children with SAM exhibited a robust