title: Plasma Tryptophan and the Kynurenine-Tryptophan Ratio are Associated with the Acquisition of Statural Growth Deficits and Oral Vaccine Underperformance in Populations with Environmental Enteropathy.
abstract: Early childhood enteric infections have adverse impacts on child growth and can inhibit normal mucosal responses to oral vaccines, two critical components of environmental enteropathy. To evaluate the role of indoleamine 2,3-dioxygenase 1 (IDO1) activity and its relationship with these outcomes, we measured tryptophan and the kynurenine-tryptophan ratio (KTR) in two longitudinal birth cohorts with a high prevalence of stunting. Children in rural Peru and Tanzania (N = 494) contributed 1,251 plasma samples at 3, 7, 15, and 24 months of age and monthly anthropometrics from 0 to 36 months of age. Tryptophan concentrations were directly associated with linear growth from 1 to 8 months after biomarker assessment. A 1-SD increase in tryptophan concentration was associated with a gain in length-for-age Z-score (LAZ) of 0.17 over the next 6 months in Peru (95% confidence interval [CI] = 0.11-0.23, P < 0.001) and a gain in LAZ of 0.13 Z-scores in Tanzania (95% CI = 0.03-0.22, P = 0.009). Vaccine responsiveness data were available for Peru only. An increase in kynurenine by 1 μM was associated with a 1.63 (95% CI = 1.13-2.34) increase in the odds of failure to poliovirus type 1, but there was no association with tetanus vaccine response. A KTR of 52 was 76% sensitive and 50% specific in predicting failure of response to serotype 1 of the oral polio vaccine. KTR was associated with systemic markers of inflammation, but also interleukin-10, supporting the association between IDO1 activity and immunotolerance. These results strongly suggest that the activity of IDO1 is implicated in the pathophysiology of environmental enteropathy, and demonstrates the utility of tryptophan and kynurenine as biomarkers for this syndrome, particularly in identifying those at risk for hyporesponsivity to oral vaccines.
authors: Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland.
authors: Margaret N
authors: MN
authors: Kosek
authors: Global Health Research Center, Haydom Lutheran Hospital, Manyara, Tanzania.
authors: Estomih
authors: E
authors: Mduma
authors: Pain Consultants of Oregon, Eugene, Oregon.
authors: Peter S
authors: PS
authors: Kosek
authors: Department of Global Community Health and Behavioral Sciences, Tulane University, New Orleans, Louisiana.
authors: Gwenyth O
authors: GO
authors: Lee
authors: Haukeland University Hospital, Bergen, Norway.
authors: Erling
authors: E
authors: Svensen
authors: Duke Global Health Institute, Nicholas School of Environment, Duke University, Durham, North Carolina.
authors: William K Y
authors: WKY
authors: Pan
authors: Asociacion Benefica Proyectos de Informática, Salud, Medicina, y Agricultura (PRISMA), Iquitos, Peru.
authors: Maribel Paredes
authors: MP
authors: Olortegui
authors: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors: Jay H
authors: JH
authors: Bream
authors: Department of Women, Children, and Family Health Science, University of Illinois at Chicago College of Nursing, Chicago, Illinois.
authors: Crystal
authors: C
authors: Patil
authors: Universidad Científica del Peru, Iquitos, Peru.
authors: Cesar Ramal
authors: CR
authors: Asayag
authors: School of Medicine, Universidad Nacional de la Amazonia Peruana, Iquitos, Peru.
authors: Graciela Meza
authors: GM
authors: Sanchez
authors: Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland.
authors: Laura E
authors: LE
authors: Caulfield
authors: Center for Global Health, University of Virginia, Charlottesville, Virginia.
authors: Jean
authors: J
authors: Gratz
authors: Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland.
authors: Pablo Peñataro
authors: PP
authors: Yori
mesh_terms: D000886:Anthropometry; D000906:Antibodies / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D002657:Child Development; D002675:Child, Preschool; D002956:Citrulline / Q000097:blood*; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology; D004751:Enteritis / Q000097:blood* / Q000276:immunology; D005260:Female; D006130:Growth Disorders / Q000097:blood* / Q000276:immunology; D006801:Humans; D007223:Infant; D007249:Inflammation; D007737:Kynurenine / Q000097:blood*; D016014:Linear Models; D008297:Male; D010568:Peru; D011055:Poliovirus Vaccine, Oral / Q000276:immunology / Q000627:therapeutic use*; D013636:Tanzania; D013745:Tetanus Toxoid / Q000276:immunology / Q000627:therapeutic use*; D014364:Tryptophan / Q000097:blood*
chemical_list: D000906:Antibodies; D000914:Antibodies, Viral; D016207:Cytokines; D011055:Poliovirus Vaccine, Oral; D013745:Tetanus Toxoid; D002956:Citrulline; D007737:Kynurenine; D014364:Tryptophan