Biomarkers of Environmental Enteropathy, Inflammation, Stunting, and Impaired Growth in Children in Northeast Brazil

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.

Protein Malnutrition Alters Tryptophan and Angiotensin-Converting Enzyme 2 Homeostasis and Adaptive Immune Responses in Human Rotavirus-Infected Gnotobiotic Pigs with Human Infant Fecal Microbiota Transplant

“…Furthermore, children at high risk for stunting often have limited tryptophan in their diets (36), and it has been shown previously that stunted children have lower serum concentrations of all nine essential amino acids, including tryptophan (37). Low plasma tryptophan is a predictor of poorer subsequent growth in boys and is associated with biomarkers of barrier disruption and intestinal and systemic inflammation in children of both genders (38). Tryptophan catabolism via the indoleamine 2,3-dioxygenase (IDO) pathway has immunoregulatory effects, and its depletion has been well studied in the context of chronic infections (39); however, the interrelationship between tryptophan and the adaptive immune response to RV and other acute infections is less clear, particularly in the context of host protein malnutrition.…”

Measurement of Gut Permeability Using Fluorescent Tracer agent Technology

“…For screening purposes, i.e., detecting increased gut permeability before clinical manifestations ensue, children at risk of environmental enteropathy and enteric dysfunction could conceivably be identified in advance of growth faltering. While some biomarkers for childhood environmental enteropathy show promise in cohort studies, they obligate recovery and analysis of urine, blood, or stool [22][23][24][25] . Small bowel biopsies, which might also be informative, are impractical in field settings.…”

Biomarkers to Stratify Risk Groups among Children with Malnutrition in Resource-Limited Settings and to Monitor Response to Intervention

“…As biomarkers of intestinal mucosal function, the L:M or L:R test may be useful for the diagnosis of perturbations in intestinal permeability and may identify children at risk of linear growth faltering [25, 26]. However, current urinary assays measuring excretion of sugars are time intensive and difficult to standardize, and population reference values are often not established [25].…”

“…In addition, these biomarkers may have different utility in interventional studies. Elevated neopterin and elevated myeloperoxidase appear to identify children at risk of subsequent growth failure, while persistently elevated neopterin with a decline in myeloperoxidase may be predictive of improvements in growth [26]. Markers reflective of increased reparative processes in the gut may also suggest an increased risk of morbidity.…”

“…The combination of these 3 biomarkers explained 56% of linear growth faltering in this population [15, 32]. A recent study in Brazil also observed that stunted infants had significantly higher plasma IgA antibodies to lipopolysaccharide and bacterial flagellin proteins, suggesting that previous exposure to bacterial translocation is associated with poor linear growth [26]. Markers reflecting catabolic processes related to low-level systemic endotoxin tolerance may also suggest a risk of other morbidities associated with stunting.…”