Putative Biomarkers of Environmental Enteric Disease Fail to Correlate in a Cross-Sectional Study in Two Study Sites in Sub-Saharan Africa

Abstract

Environmental enteric dysfunction (EED) is an elusive, inflammatory syndrome of the small intestine thought to be associated with enterocyte loss and gut leakiness and lead to stunted child growth. To date, the gold standard for diagnosis is small intestine biopsy followed by histology. Several putative biomarkers for EED have been proposed and are widely used in the field. Here, we assessed in a cross-sectional study of children aged 2–5 years for a large set of biomarkers including markers of protein exudation (duodenal and fecal alpha-1-antitrypsin (AAT)), inflammation (duodenal and fecal calprotectin, duodenal, fecal and blood immunoglobulins, blood cytokines, C-reactive protein (CRP)), gut permeability (endocab, lactulose-mannitol ratio), enterocyte mass (citrulline) and general nutritional status (branched-chain amino acids (BCAA), insulin-like growth factor) in a group of 804 children in two Sub-Saharan countries. We correlated these markers with each other and with anemia in stunted and non-stunted children. AAT and calprotectin, CRP and citrulline and citrulline and BCAA correlated with each other. Furthermore, BCAA, citrulline, ferritin, fecal calprotectin and CRP levels were correlated with hemoglobin levels. Our results show that while several of the biomarkers are associated with anemia, there is little correlation between the different biomarkers. Better biomarkers and a better definition of EED are thus urgently needed.

Association of endotoxaemia with low grade inflammation, metabolic syndrome and distinct response to lipopolysaccharide in type 1 diabetes

“…This was anticipated, as in the majority of study participants, faecal calprotectin was in the normal range (< 50 mg/g), excluding severe bowel in ammation which could contribute to systemic in ammation. Thus our data con rm that calprotectin can not serve as a universal enteric dysfunction marker, as reported previously 54 .…”

Effect of an onsite shared sanitation intervention on markers of environmental enteric dysfunction in children living in Maputo, Mozambique

“…However, the biomarkers we measured, which represent a fraction of candidate markers, may not provide a comprehensive accounting of a child's EED status as they only measure two of the five domains of EED (14). While there is limited agreement on ideal biomarkers of EED (10,14,35), it is widely accepted that a panel of markers is likely necessary to describe the pathophysiology of EED.…”

Maternal malnutrition induces in the neonate a lifelong enteropathy avoidable by postnatal S100a8/a9-conditioning

“…EE is characterized by chronic gut inflammation, villus blunting and impaired barrier function leading to malabsorption that in turn further aggravates malnutrition, catching affected individuals in a vicious cycle [9][10][11] . Since EE is primarily diagnosed in patients living in poor and unsanitary conditions 9,12 , frequent uptake of pathogens and altered intestinal colonization are discussed to induce EE [13][14][15][16][17][18] . In mouse models that start PEM after weaning, additional microbial challenges or intestinal injuries are required as co-impulses to induce EE 19,20 .…”