Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea

Background
Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia.
Methods/Principal findings
We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy.
Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013).
Conclusions/Significance
Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization.

背景
环境性肠功能障碍（Environmental enteric dysfunction, EED）在热带地区广泛流行，在儿童群体中与发育迟缓及其他不良健康结局密切相关。肠病的标志性特征之一为绒毛损伤。在患有重度急性营养不良（Severe Acute Malnutrition, SAM）的儿童中，肠病的严重程度更高，短期死亡率居高不下，但目前学界对于肠病所带来的代谢结局仍尚不明确。本研究针对赞比亚重度营养不良儿童，分析其尿液代谢组改变与绒毛健康状态、经典肠病生物标志物以及人体测量学指标之间的关联。
方法与主要研究结果
本研究纳入赞比亚20名6~23月龄的急性营养不良住院儿童。对其中15名儿童的小肠活检组织进行组织学评估，收集人体测量学数据与肠道功能指标，并通过氢质子核磁共振（1H nuclear magnetic resonance, NMR）波谱分析其代谢表型。
社区对照儿童无法接受内镜检查。生长参数与肠病生物标志物呈负相关（p=0.011）；绒毛健康相关参数与易位及通透性生物标志物亦呈负相关（p分别为0.000与0.015）。绒毛高度降低与肠道微生物代谢、能量代谢及肌肉代谢相关代谢物丰度下降显著相关（p=0.034）。绒毛变钝还与蔗糖排泄量增加存在关联（p=0.013）。
结论与意义
肠道绒毛变钝与重度营养不良住院儿童的多项代谢紊乱密切相关。这些改变包括肌肉代谢异常，进一步证实了环境性肠功能障碍与生长迟缓之间的关联，同时也反映了肠道菌群与宿主之间的生化交换受到破坏。本研究结果加深了学界对肠道绒毛变钝下游效应的理解，并为肠功能障碍提供了全新的非侵入性生物标志物。本研究的主要局限性在于缺乏可比照的对照组，且未对肠道菌群进行表征分析。