{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T19:05:27Z","timestamp":1787252727477,"version":"build-2736575974"},"reference-count":45,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,5]]},"abstract":"<jats:p>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\u2013tryptophan ratio (KTR) in two longitudinal birth cohorts with a high prevalence of stunting. Children in rural Peru and Tanzania (<jats:italic>N<\/jats:italic> = 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\u20130.23, <jats:italic>P<\/jats:italic> &lt; 0.001) and a gain in LAZ of 0.13 Z-scores in Tanzania (95% CI = 0.03\u20130.22, <jats:italic>P<\/jats:italic> = 0.009). Vaccine responsiveness data were available for Peru only. An increase in kynurenine by 1 \u03bcM was associated with a 1.63 (95% CI = 1.13\u20132.34) 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.<\/jats:p>","DOI":"10.4269\/ajtmh.16-0037","type":"journal-article","created":{"date-parts":[[2016,8,9]],"date-time":"2016-08-09T03:13:38Z","timestamp":1470712418000},"page":"928-937","source":"Crossref","is-referenced-by-count":72,"title":["Plasma Tryptophan and the Kynurenine\u2013Tryptophan Ratio are Associated with the Acquisition of Statural Growth Deficits and Oral Vaccine Underperformance in Populations with Environmental Enteropathy"],"prefix":"10.4269","volume":"95","author":[{"given":"Margaret N.","family":"Kosek","sequence":"first","affiliation":[{"name":"1Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estomih","family":"Mduma","sequence":"additional","affiliation":[{"name":"2Global Health Research Center, Haydom Lutheran Hospital, Manyara, Tanzania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Kosek","sequence":"additional","affiliation":[{"name":"3Pain Consultants of Oregon, Eugene, Oregon."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwenyth O.","family":"Lee","sequence":"additional","affiliation":[{"name":"4Department of Global Community Health and Behavioral Sciences, Tulane University, New Orleans, Louisiana."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erling","family":"Svensen","sequence":"additional","affiliation":[{"name":"5Haukeland University Hospital, Bergen, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William K. Y.","family":"Pan","sequence":"additional","affiliation":[{"name":"6Duke Global Health Institute, Nicholas School of Environment, Duke University, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maribel Paredes","family":"Olortegui","sequence":"additional","affiliation":[{"name":"7Asociacion Benefica Proyectos de Inform\u00e1tica, Salud, Medicina, y Agricultura (PRISMA), Iquitos, Peru."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay H.","family":"Bream","sequence":"additional","affiliation":[{"name":"8Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Patil","sequence":"additional","affiliation":[{"name":"9Department of Women, Children, and Family Health Science, University of Illinois at Chicago College of Nursing, Chicago, Illinois."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar Ramal","family":"Asayag","sequence":"additional","affiliation":[{"name":"10Universidad Cient\u00edfica del Peru, Iquitos, Peru."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela Meza","family":"Sanchez","sequence":"additional","affiliation":[{"name":"11School of Medicine, Universidad Nacional de la Amazonia Peruana, Iquitos, Peru."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Caulfield","sequence":"additional","affiliation":[{"name":"1Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Gratz","sequence":"additional","affiliation":[{"name":"12Center for Global Health, University of Virginia, Charlottesville, Virginia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo Pe\u00f1ataro","family":"Yori","sequence":"additional","affiliation":[{"name":"1Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2795","reference":[{"issue":"(Suppl 4)","key":"ref1","series-title":"Clin Infect Dis","first-page":"S239","article-title":"Assessment of environmental enteropathy in the MAL-ED cohort study: theoretical and analytical framework","volume":"59","author":"Kosek","year":"2014"},{"key":"ref2","series-title":"EBioMedicine","first-page":"1759","article-title":"Environmental enteropathy, oral vaccine failure and growth faltering in infants in Bangladesh","volume":"2","author":"Naylor","year":"2015"},{"key":"ref3","series-title":"Am J Trop Med Hyg","first-page":"412","article-title":"Responses of small intestinal architecture and function over time to environmental factors in a tropical population","volume":"70","author":"Kelly","year":"2004"},{"key":"ref4","series-title":"Am J Clin Nutr","first-page":"1040","article-title":"Effect of Lactobacillus GG on intestinal integrity in Malawian children at risk of tropical enteropathy","volume":"82","author":"Galpin","year":"2005"},{"key":"ref5","series-title":"Lancet","first-page":"1032","article-title":"Child undernutrition, tropical enteropathy, toilets, and handwashing","volume":"374","author":"Humphrey","year":"2009"},{"key":"ref6","series-title":"Lancet Glob Health","first-page":"e564","article-title":"Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED)","volume":"3","author":"Platts-Mills","year":"2015"},{"key":"ref7","series-title":"Immunol Cell Biol","first-page":"303","article-title":"Immunometabolism: the interface of immune and metabolic responses in disease","volume":"92","author":"Schertzer","year":"2014"},{"key":"ref8","series-title":"Trends Immunol","first-page":"137","article-title":"Indoleamine 2,3 dioxygenase and metabolic control of immune responses","volume":"34","author":"Munn","year":"2013"},{"key":"ref9","series-title":"J Immunol","first-page":"7243","article-title":"Endotoxin tolerance represents a distinctive state of alternative polarization (M2) in human mononuclear cells","volume":"186","author":"Pena","year":"2011"},{"key":"ref10","series-title":"Proc Soc Exp Biol Med","first-page":"248","article-title":"Development of tolerance to typhoid bacterial pathogen and its abolition by reticulo-endothelial cell blockade","volume":"61","author":"Beeson","year":"1946"},{"key":"ref11","series-title":"Blood","first-page":"1341","article-title":"Downregulation of proinflammatory cytokine release in whole blood from septic patients","volume":"85","author":"Ertel","year":"1995"},{"issue":"(Suppl 4)","key":"ref12","series-title":"Clin Infect Dis","first-page":"S220","article-title":"Disease surveillance methods used in the 8-site MAL-ED cohort study","volume":"59","author":"Richard","year":"2014"},{"issue":"(Suppl 4)","key":"ref13","series-title":"Clin Infect Dis","first-page":"S310","article-title":"Santa Clara de Nanay: the MAL-ED cohort in Peru","volume":"59","author":"Yori","year":"2014"},{"issue":"(Suppl 4)","key":"ref14","series-title":"Clin Infect Dis","first-page":"S325","article-title":"The etiology, risk factors, and interactions of enteric infections and malnutrition and the consequences for child health and development study (MAL-ED): description of the Tanzanian site","volume":"59","author":"Mduma","year":"2014"},{"key":"ref15","series-title":"Acta Paediatr Suppl","first-page":"76","article-title":"WHO child growth standards based on length\/height, weight and age","volume":"450","author":"WHO Multicentre Growth Reference Study Group","year":"2006"},{"key":"ref16","series-title":"Braz J Med Biol Res","first-page":"1499","article-title":"Measurement of intestinal permeability using mannitol and lactulose in children with diarrheal diseases","volume":"32","author":"Barboza","year":"1999"},{"key":"ref17","series-title":"J Pediatr Gastroenterol Nutr","first-page":"544","article-title":"Lactulose: mannitol diagnostic test by HPLC and LC-MSMS platforms: considerations for field studies of intestinal barrier function and environmental enteropathy","volume":"59","author":"Lee","year":"2014"},{"key":"ref18","series-title":"Cytokine","first-page":"661","article-title":"Differential serum cytokine responses to inactivated and live attenuated seasonal influenza vaccines","volume":"60","author":"Ramakrishnan","year":"2012"},{"key":"ref19","series-title":"Am J Clin Nutr","first-page":"1582","article-title":"Relation of serum retinol to acute phase proteins and malarial morbidity in Papua New Guinea children","volume":"71","author":"Rosales","year":"2000"},{"key":"ref20","series-title":"Manual for the Virological Investigation of Poliomyelitis","author":"World Health Organization (WHO)","year":"1997"},{"key":"ref21","series-title":"The Immunological Basis of Immunization Series: Tetanus Update 2006","author":"Borrow","year":"2007"},{"key":"ref22","series-title":"J Acquir Immune Defic Syndr","first-page":"397","article-title":"Preventing mother to child transmission of HIV with highly active antiretroviral treatment in Tanzania: a prospective cost-effectiveness study","volume":"55","author":"Robberstad","year":"2010"},{"key":"ref23","series-title":"Lancet","first-page":"1804","article-title":"Effects of early childhood psychosocial stimulation and nutritional supplementation on cognition and education in growth-stunted Jamaican children: prospective cohort study","volume":"366","author":"Walker","year":"2005"},{"key":"ref24","series-title":"Lancet","first-page":"60","article-title":"Developmental potential in the first 5 years for children in developing countries","volume":"369","author":"Grantham-McGregor","year":"2007"},{"key":"ref25","series-title":"J Public Econ","first-page":"345","article-title":"Early childhood nutrition and academic achievement: a longitudinal analysis","volume":"81","author":"Glewwe","year":"2001"},{"key":"ref26","series-title":"Econ Hum Biol","first-page":"114","article-title":"Inferring the economic standard of living and health from cohort height: evidence from modern populations in developing countries","volume":"19","author":"Akachi","year":"2015"},{"key":"ref27","series-title":"Am J Trop Med Hyg","first-page":"390","article-title":"Fecal markers of intestinal inflammation and permeability associated with the subsequent acquisition of linear growth deficits in infants","volume":"88","author":"Kosek","year":"2013"},{"key":"ref28","series-title":"FASEB J","first-page":"403.5","article-title":"Serum citrulline does not predict stunting or environmental enteric dysfunction in Tanzanian and Malawian infants","volume":"29","author":"Gosselin","year":"2015"},{"key":"ref29","series-title":"J Pediatr Gastroenterol Nutr","first-page":"348","article-title":"Associations between intestinal mucosal function and changes in plasma zinc concentration following zinc supplementation","volume":"57","author":"Wessells","year":"2013"},{"key":"ref30","series-title":"Morb Mortal Wkly Rep","first-page":"913","article-title":"World Health Organization guidelines for containment of poliovirus following type-specific polio eradication: worldwide, 2015","volume":"64","author":"Previsani","year":"2015"},{"key":"ref31","series-title":"Nat Rev Immunol","first-page":"762","article-title":"IDO expression by dendritic cells: tolerance and tryptophan catabolism","volume":"4","author":"Mellor","year":"2004"},{"key":"ref32","series-title":"J Histochem Cytochem","first-page":"17","article-title":"Indoleamine 2,3-dioxygenase tissue distribution and cellular localization in mice: implications for its biological functions","volume":"58","author":"Dai","year":"2010"},{"key":"ref33","series-title":"Inflamm Bowel Dis","first-page":"1214","article-title":"Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity","volume":"18","author":"Gupta","year":"2012"},{"key":"ref34","series-title":"Immunity","first-page":"372","article-title":"Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22","volume":"39","author":"Zelante","year":"2013"},{"key":"ref35","series-title":"Sci Transl Med","first-page":"32ra36","article-title":"Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of Th17 to regulatory T cells in HIV disease","volume":"2","author":"Favre","year":"2010"},{"key":"ref36","series-title":"Clin Gastroenterol Hepatol","first-page":"754","article-title":"A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease","volume":"4","author":"Braat","year":"2006"},{"key":"ref37","series-title":"J Nutr","first-page":"2231S","article-title":"Lessons learned regarding symptoms of tryptophan deficiency and excess from animal requirement studies","volume":"142","author":"Moehn","year":"2012"},{"key":"ref38","series-title":"Clin Chem","first-page":"2397","article-title":"Age-specific distribution of plasma amino acid concentrations in a healthy pediatric population","volume":"43","author":"Lepage","year":"1997"},{"key":"ref39","series-title":"Adv Nutr","first-page":"217","article-title":"Quality protein maize for Africa: closing the protein inadequacy gap in vulnerable populations","volume":"2","author":"Nuss","year":"2011"},{"key":"ref40","series-title":"Food Nutr Bull","first-page":"445","article-title":"The quality protein maize story","volume":"21","author":"Vasal","year":"2000"},{"key":"ref41","series-title":"ISME J","first-page":"1933","article-title":"A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice","volume":"7","author":"Marcobal","year":"2013"},{"key":"ref42","series-title":"J Nutr","first-page":"51","article-title":"Dietary amino acid deficiency reduces the utilization of amino acids for growth in growing pigs after a period of poor health","volume":"146","author":"Kampman-van de Hoek","year":"2016"},{"key":"ref43","series-title":"Animal","first-page":"1891","article-title":"A moderate inflammation caused by the deterioration of housing conditions modifies Trp metabolism but not Trp requirement for growth of post-weaned piglets","volume":"4","author":"Le Floc'h","year":"2010"},{"key":"ref44","series-title":"J Anim Sci","first-page":"3485","article-title":"Immune system stimulation reduces the efficiency of tryptophan utilization for body protein deposition in growing pigs","volume":"90","author":"de Ridder","year":"2012"},{"key":"ref45","series-title":"J Nutr","first-page":"906","article-title":"Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states?","volume":"124","author":"Reeds","year":"1994"}],"container-title":["The American Society of Tropical Medicine and Hygiene"],"original-title":[],"link":[{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/95\/4\/article-p928.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/95\/4\/article-p928.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/95\/4\/article-p928.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T21:54:45Z","timestamp":1723067685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/95\/4\/article-p928.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,5]]},"references-count":45,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.4269\/ajtmh.16-0037","relation":{},"ISSN":["0002-9637","1476-1645"],"issn-type":[{"value":"0002-9637","type":"print"},{"value":"1476-1645","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,5]]}}}