Abstract
Critical to the design and assessment of interventions for enteropathy and its developmental consequences in children living in impoverished conditions are non-invasive biomarkers that can detect intestinal damage and predict its effects on growth and development. We therefore assessed fecal, urinary and systemic biomarkers of enteropathy and growth predictors in 375 6–26 month-old children with varying degrees of malnutrition (stunting or wasting) in Northeast Brazil. 301 of these children returned for followup anthropometry after 2-6m. Biomarkers that correlated with stunting included plasma IgA anti-LPS and anti-FliC, zonulin (if >12m old), and intestinal FABP (I-FABP, suggesting prior barrier disruption); and with citrulline, tryptophan and with lower serum amyloid A (SAA) (suggesting impaired defenses). In contrast, subsequent growth was predicted in those with higher fecal MPO or A1AT and also by higher L/M, plasma LPS, I-FABP and SAA (showing intestinal barrier disruption and inflammation). Better growth was predicted in girls with higher plasma citrulline and in boys with higher plasma tryptophan. Interactions were also seen with fecal MPO and neopterin in predicting subsequent growth impairment.Biomarkers clustered into markers of 1) functional intestinal barrier disruption and translocation, 2) structural intestinal barrier disruption and inflammation and 3) systemic inflammation. Principle components pathway analyses also showed that L/M with %L, I-FABP and MPO associate with impaired growth, while also (like MPO) associating with a systemic inflammation cluster of kynurenine, LBP, sCD14, SAA and K/T. Systemic evidence of LPS translocation associated with stunting, while markers of barrier disruption or repair (A1AT and Reg1 with low zonulin) associated with fecal MPO and neopterin.We conclude that key noninvasive biomarkers of intestinal barrier disruption, LPS translocation and of intestinal and systemic inflammation can help elucidate how we recognize, understand, and assess effective interventions for enteropathy and its growth and developmental consequences in children in impoverished settings.
Highlights
Children living in impoverished areas around the world often develop stunted growth from 4 to 24 months of age, a concern that is heightened by potential lasting consequences of impaired cognitive development [1,2,3,4,5]
Several plasma biomarkers suggesting prior intestinal barrier disruption were significantly correlated with stunting or wasting, as assessed by height for age Z score (HAZ) or weight for age Z score (WAZ) at study start, respectively, in children when they were first enrolled
Subsequent growth was significantly worse in those with higher fecal MPO or A1AT (Fig 2A and 2B), and growth impairment correlated with higher L/M, LPS, intestinal fatty acid binding protein (I-FABP) and serum amyloid A (SAA) (Fig 1 and Fig 2C–2F) in showing fecal and systemic markers of intestinal inflammation and barrier disruption or enteropathy)
Summary
Children living in impoverished areas around the world often develop stunted growth from 4 to 24 months of age, a concern that is heightened by potential lasting consequences of impaired cognitive development [1,2,3,4,5]. Sensitive detection methods are revealing that multiple and repeated intestinal infections are even more common (with and without overt diarrheal illnesses) in young children living in impoverished areas lacking in adequate sanitation or clean water [6, 7] These heavy pathogen burdens may associate with growth faltering or cognitive impairment [8,9,10,11,12,13,14]. Undernutrition is common and may further worsen the impact of enteric infections on growth and development, leading to a potential “vicious cycle” of malnutrition and enteric infections [15,16,17] These potential relationships can be causally dissected in animal models, where certain enteric infections, such as Cryptosporidium or enteroaggregative Escherichia coli [18, 19] or even certain mixed Bacteroidetes and Proteobacteria [20] can further worsen the growth impairment and intestinal damage in undernourished states. Our objective was to examine a wide range of potential fecal, urinary and plasma biomarkers to determine how they associate with each other and with malnutrition (defined by height or weight for age) and to determine which ones best predict impaired subsequent growth
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