Kosek Margaret N, Mduma Estomih, Kosek Peter S, Lee Gwenyth O, Svensen Erling, Pan William K Y, Olortegui Maribel Paredes, Bream Jay H, Patil Crystal, Asayag Cesar Ramal, Sanchez Graciela Meza, Caulfield Laura E, Gratz Jean, Yori Pablo Peñataro
Department of International Health, Johns Hopkins School of Public Health, Baltimore, Maryland.
Global Health Research Center, Haydom Lutheran Hospital, Manyara, Tanzania.
Am J Trop Med Hyg. 2016 Oct 5;95(4):928-937. doi: 10.4269/ajtmh.16-0037. Epub 2016 Aug 8.
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.
幼儿肠道感染会对儿童生长产生不利影响，并可能抑制对口服疫苗的正常黏膜反应，这是环境性肠病的两个关键因素。为了评估吲哚胺2,3-双加氧酶1（IDO1）活性的作用及其与这些结果的关系，我们在两个发育迟缓患病率较高的纵向出生队列中测量了色氨酸和犬尿氨酸-色氨酸比值（KTR）。秘鲁农村和坦桑尼亚的儿童（N = 494）在3、7、15和24月龄时提供了1251份血浆样本，并在0至36月龄时每月进行人体测量。在生物标志物评估后的1至8个月内，色氨酸浓度与线性生长直接相关。色氨酸浓度每增加1个标准差，秘鲁儿童在接下来的6个月内年龄别身长Z评分（LAZ）增加0.17（95%置信区间[CI]=0.11-0.23，P<0.001），坦桑尼亚儿童的LAZ增加0.13个Z评分（95%CI = 0.03-0.22，P = 0.009）。疫苗反应性数据仅来自秘鲁。犬尿氨酸每增加1μM，1型脊髓灰质炎病毒免疫失败几率增加1.63倍（95%CI = 1.13-2.34），但与破伤风疫苗反应无关。KTR为52时，预测口服脊髓灰质炎疫苗1型血清型免疫失败的敏感性为76%，特异性为50%。KTR与炎症的全身标志物相关，但也与白细胞介素-10相关，支持IDO1活性与免疫耐受之间的关联。这些结果有力地表明，IDO1的活性与环境性肠病的病理生理学有关，并证明色氨酸和犬尿氨酸作为该综合征生物标志物的实用性，特别是在识别对口服疫苗低反应性风险人群方面。
