From the Edison Family Center for Genome Sciences and Systems Biology (R.Y.C., V.L.K., M.C.H., J.G., B.D.L., K.A., E.K., J.S.-B., M.J.B., J.I.G.), the Center for Gut Microbiome and Nutrition Research (R.Y.C., V.L.K., M.C.H., J.G., K.A., M.J.B., J.I.G.), and the Department of Pathology and Immunology (V.L.K., M.J.B., J.I.G.), Washington University School of Medicine, St. Louis; the International Center for Diarrhoeal Disease Research, Bangladesh (S.D., M.S.H., M.M., S.M.F., M.A.G., R.H., S.A.S., R.N.M., T.A.), the Department of Pathology, Dr. Sirajul Islam Medical College (S.M.K.N.B.), and Sheikh Russel National Gastroliver Institute and Hospital (M.M.R.), Dhaka, Bangladesh; the A.A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow (D.A.R., S.A.L.); and the Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (D.A.R., S.A.L., A.L.O.).
N Engl J Med. 2020 Jul 23;383(4):321-333. doi: 10.1056/NEJMoa1916004.
Environmental enteric dysfunction (EED) is an enigmatic disorder of the small intestine that is postulated to play a role in childhood undernutrition, a pressing global health problem. Defining the incidence of this disorder, its pathophysiological features, and its contribution to impaired linear and ponderal growth has been hampered by the difficulty in directly sampling the small intestinal mucosa and microbial community (microbiota).
In this study, among 110 young children (mean age, 18 months) with linear growth stunting who were living in an urban slum in Dhaka, Bangladesh, and had not benefited from a nutritional intervention, we performed endoscopy in 80 children who had biopsy-confirmed EED and available plasma and duodenal samples. We quantified the levels of 4077 plasma proteins and 2619 proteins in duodenal biopsy samples obtained from these children. The levels of bacterial strains in microbiota recovered from duodenal aspirate from each child were determined with the use of culture-independent methods. In addition, we obtained 21 plasma samples and 27 fecal samples from age-matched healthy children living in the same area. Young germ-free mice that had been fed a Bangladeshi diet were colonized with bacterial strains cultured from the duodenal aspirates.
Of the bacterial strains that were obtained from the children, the absolute levels of a shared group of 14 taxa (which are not typically classified as enteropathogens) were negatively correlated with linear growth (length-for-age z score, r = -0.49; P = 0.003) and positively correlated with duodenal proteins involved in immunoinflammatory responses. The representation of these 14 duodenal taxa in fecal microbiota was significantly different from that in samples obtained from healthy children (P<0.001 by permutational multivariate analysis of variance). Enteropathy of the small intestine developed in gnotobiotic mice that had been colonized with cultured duodenal strains obtained from children with EED.
These results provide support for a causal relationship between growth stunting and components of the small intestinal microbiota and enteropathy and offer a rationale for developing therapies that target these microbial contributions to EED. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02812615.).
肠病相关的肠黏膜损伤（EED）是一种神秘的小肠功能紊乱，被认为与儿童时期的营养不良有关，而营养不良是当前全球面临的一个严重健康问题。由于难以直接采样小肠黏膜和微生物群落（微生物组），因此一直未能明确界定这种疾病的发病率、病理生理学特征以及其对线性和体重生长受损的影响。
在本项研究中，我们对居住在孟加拉国达卡市贫民窟、年龄为 18 个月且尚未接受营养干预的 110 名生长迟缓的幼儿进行了研究，其中 80 名经内镜活检证实患有 EED 且有可利用的血浆和十二指肠样本的儿童接受了内镜检查。我们对这些儿童的血浆样本定量分析了 4077 种蛋白和十二指肠活检样本中的 2619 种蛋白。采用非培养方法测定从每个儿童十二指肠抽吸物中回收的微生物群中细菌株的水平。此外，我们还从生活在同一地区的 21 名年龄匹配的健康儿童中获得了 27 份粪便样本。使用从十二指肠抽吸物中培养的细菌株对喂食孟加拉国饮食的无菌幼鼠进行定植。
从儿童中获得的细菌株中，一组 14 种（通常不被归类为肠病原体）共同细菌株的绝对水平与线性生长（年龄别身长 Z 评分，r = -0.49；P = 0.003）呈负相关，与参与免疫炎症反应的十二指肠蛋白呈正相关。这些 14 种十二指肠细菌群在粪便微生物群中的表现与从健康儿童中获得的样本明显不同（通过置换多元方差分析，P<0.001）。定植了从 EED 儿童中获得的培养十二指肠菌株的无菌小鼠出现了小肠肠炎。
这些结果为生长迟缓与小肠微生物群和肠炎的组成部分之间存在因果关系提供了支持，并为开发针对这些微生物对 EED 贡献的治疗方法提供了依据。（由比尔及梅琳达·盖茨基金会等资助；ClinicalTrials.gov 注册号：NCT02812615。）
