TY - JOUR
T1 - Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in northeast Brazil
AU - Guerrant, Richard L.
AU - Leite, Alvaro M.
AU - Pinkerton, Relana
AU - Medeiros, Pedro H.Q.S.
AU - Cavalcante, Paloma A.
AU - DeBoer, Mark
AU - Kosek, Margaret
AU - Duggan, Christopher
AU - Gewirtz, Andrew
AU - Kagan, Jonathan C.
AU - Gauthier, Anna E.
AU - Swann, Jonathan
AU - Mayneris-Perxachs, Jordi
AU - Bolick, David T.
AU - Maier, Elizabeth A.
AU - Guedes, Marjorie M.
AU - Moore, Sean R.
AU - Petri, William A.
AU - Havt, Alexandre
AU - Lima, Ila F.
AU - De Prata, Mara Moura Gondim
AU - Michaleckyj, Josyf C.
AU - Scharf, Rebecca J.
AU - Sturgeon, Craig
AU - Fasano, Alessio
AU - Lima, Aldo A.M.
N1 - Funding Information:
This work was supported by the Bill & Melinda Gates Foundation Biomarker Grants No. OPP1066140 entitled, "Novel metabonomic biomarkers of gut function and health: Modeling enteropathy (EE) and field validation”, and in part by OPP 1066146 and OPP 1099111 “Production of a Reg1B fecal enzyme immunoassay as a potential biomarker of childhood stunting,” by the NIH grant DK048373 entitled “Zot, Zonulin, and Pathophysiology of Intestinal Tight Junctions, by NIH grant K02TW008767, and in part as a case-control component of the “Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development” Project (MAL-ED) carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the NIH, and the National Institutes of Health, Fogarty International Center. The authors thank the staff and participants of the MAL-ED Network for their important contributions. No authors declare a conflict of interest. RJS has a Clinical Scientist Development Award from the Doris Duke Charitable Foundation.
Publisher Copyright:
© 2016 Guerrant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/9
Y1 - 2016/9
N2 - 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 intes tinal 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.
AB - 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 intes tinal 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.
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U2 - 10.1371/journal.pone.0158772
DO - 10.1371/journal.pone.0158772
M3 - Article
C2 - 27690129
AN - SCOPUS:84991781199
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 9
M1 - e0158772
ER -