Biomarkers of Environmental Enteropathy, Inflammation, Stunting, and Impaired Growth in Children in Northeast Brazil.
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.
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
Richard L
RL
Guerrant
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Alvaro M
AM
Leite
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
Relana
R
Pinkerton
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Pedro H Q S
PH
Medeiros
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Paloma A
PA
Cavalcante
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
Mark
M
DeBoer
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
Margaret
M
Kosek
Division of Gastroenterology at Boston Children's Hospital, Harvard University, Boston, MA, United States of America.
Christopher
C
Duggan
Institute for Biomedical Sciences in the Center for Inflammation, Immunity and Infection at Georgia State University, Atlanta, GA, United States of America.
Andrew
A
Gewirtz
Division of Gastroenterology at Boston Children's Hospital, Harvard University, Boston, MA, United States of America.
Jonathan C
JC
Kagan
Division of Gastroenterology at Boston Children's Hospital, Harvard University, Boston, MA, United States of America.
Anna E
AE
Gauthier
Imperial College, London, United Kingdom.
Jonathan
J
Swann
Imperial College, London, United Kingdom.
Jordi
J
Mayneris-Perxachs
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
David T
DT
Bolick
Cincinnati Children's Hospital, Cincinnati, OH, United States of America.
Elizabeth A
EA
Maier
Cincinnati Children's Hospital, Cincinnati, OH, United States of America.
Marjorie M
MM
Guedes
Cincinnati Children's Hospital, Cincinnati, OH, United States of America.
Sean R
SR
Moore
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
William A
WA
Petri
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Alexandre
A
Havt
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Ila F
IF
Lima
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Mara de Moura Gondim
MM
Prata
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
Josyf C
JC
Michaleckyj
University of Virginia School of Medicine (Division of Infectious Diseases and International Health, Department of Medicine, Department of Pediatrics and Center for Global Health), Charlottesville, VA, United States of America.
Rebecca J
RJ
Scharf
Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition at Massachusetts General Hospital for Children, Harvard University, Boston, MA, United States of America.
Craig
C
Sturgeon
Mucosal Immunology and Biology Research Center and Division of Pediatric Gastroenterology and Nutrition at Massachusetts General Hospital for Children, Harvard University, Boston, MA, United States of America.
Alessio
A
Fasano
Clinical Research Unit, Federal University of Ceara, Fortaleza, Brazil.
Aldo A M
AA
Lima
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