New Supplement Published in The American Journal for Clinical Nutrition

Environmental enteric dysfunction is an asymptomatic acquired disorder characterized by upper small bowel inflammation, villous blunting, and gut permeability.  It is a major contributor to poor growth among children in low- and middle-income regions, as well as to other undesirable outcomes such as decreased efficacy of oral vaccines.

We are now seeing a resurgence in the field of environmental enteric dysfunction research; however, recent studies have been hampered by a lack of investigation into the target tissue, the upper small bowel.

In response, the Environmental Enteric Dysfunction Biopsy Initiative Consortium was established in 2016 as a common scientific platform across three independent biopsy cohort studies conducted in Bangladesh, Pakistan, and Zambia.  The Consortium also works with two biopsy centers in the United States in order to establish a baseline comparison group of children undergoing endoscopy for various clinical indications.  The Consortium seeks to enhance and extend the contributions of the individual centers by addressing complex questions related to environmental enteric dysfunction mucosal histology, morphometry, and immunohistochemistry.

The American Journal of Clinical Research has recently published Environmental Enteric Dysfunction Biopsy Initiative: An Intensive Prospective Multicenter Analysis, a supplement dedicated to key research findings stemming from the Consortium.  The supplement consists of seven original research articles plus an introductory article and an editorial.  For more information about the Consortium, its cohorts, and recruitment procedures, please refer to the introductory article, The Environmental Enteric Dysfunction Biopsy Initiative (EEDBI) Consortium: Mucosal Investigations of EED.

Following is a brief summary of each of the research articles published in the supplement, highlighting the authors’ key findings.

Duodenal Quantitative Mucosal Morphometry in Children with Environmental Enteric Dysfunction: A Cross-Sectional Multi-Country Analysis

Quantifying intestinal morphology in cases of environmental enteric dysfunction would help researchers explore its association with functional and disease outcomes.  In this cross-section study, morphology, histology and immunohistochemistry were assessed on duodenal biopsy slides from children with environmental enteric dysfunction and then compared to slides from children with no pathologic abnormality.  According to the findings, “morphometric analysis of duodenal biopsy slides across geographies identified morphologic features of environmental enteric dysfunction: specifically short villi, elongated crypts, and a smaller villus:crypt ratio relative to no pathologic abnormality slides.”  The authors further noted that “morphometry did not explain other environmental enteric dysfunction features, suggesting that environmental enteric dysfunction histopathologic processes may be operating independently of morphology.”

Anthropometry Relationship with Duodenal Histological Features of Children with Environmental Enteric Dysfunction: A Multicenter Cross-Sectional Study

This study examined the relationships between anthropometrics and duodenal histological features among children with environmental enteric dysfunction.  After adjusting for potential confounders, “no association was seen between height-for-age z score, weight-for-age z score, or weight-for-height z score and histology features or the summary environmental enteric dysfunction index score.”  The authors believe their study “contributes a crucial negative finding that morphological features in the duodenal tissue have no association with the anthropometric phenotypes; hence, growth measurements may not be a suitable outcome to monitor environmental enteric dysfunction when it is measured in terms of the histological features that we used.”

Multiplexed Immunohistochemical Evaluation of Small Bowel Inflammatory and Epithelial Parameters in Environmental Enteric Dysfunction

To better understand the pathophysiology of environmental enteric dysfunction, this study analyzed several panels of immunohistochemical stains among a large cohort of endoscopic biopsies of children with suboptimal growth.  The panels were then compared to cohorts of children with celiac disease or with no known enteric disease and no pathologic abnormality.  The results of the study “support a model of chronic epithelial stress that decreases epithelial differentiation and absorptive function.”  The authors further noted that “the close association of several immunohistochemistry parameters with manual histologic scoring suggests that automated digital quantification of immunohistochemistry panels complements traditional histomorphologic assessment in environmental enteric dysfunction.”

Duodenal Transcriptomics Demonstrates Signatures of Tissue Inflammation and Immune Cell Infiltration in Children with Environmental Enteric Dysfunction across Global Center

By generating RNA-sequencing libraries of duodenal tissue obtained from undernourished children with environmental enteric dysfunction, this study sought to identify dysregulated genes and pathways that might underlie pediatric environmental enteric dysfunction.  According to the study findings, “the transcriptome signatures of environmental enteric dysfunction include specific innate and adaptive immune responses that are consistently elevated across study centers, coupled with reduced detoxification and antioxidant capacities.”  The authors noted that “the strength of our work includes integration of multiple prospective study designs and use of endoscopy to collect tissue, which together offers an unprecedented insight into the small intestinal tissue transcriptome in environmental enteric dysfunction.”  Furthermore, the authors believe that “these data may have implications for targeted interventions to improve environmental enteric dysfunction outcomes.”

Histopathology Underlying Environmental Enteric Dysfunction in a Cohort Study of Undernourished Children in Bangladesh, Pakistan, and Zambia Compared with US Children

The authors of this study set out to develop and validate a scoring system, the Total Score Percent-5, that would be suitable for widespread application in research on the histopathology of environmental enteric dysfunction.  According to the findings, “five parameters were sufficient to determine the presence of environmental enteric dysfunction with a high degree of precision.”  The authors therefore “recommend the Total Score Percent-5 as a practical way of scoring biopsies from children who may have environmental enteric dysfunction and hope that this will facilitate future rigorous comparisons across populations in relation to pathogen profiles, dietary intakes, and environmental factors.”  The authors also believe that “this scoring system could be applied as an endpoint in clinical trials of novel therapies to reduce adverse consequences of environmentally-mediated gut damage.”

Biomarker Relationships with Small Bowel Histopathology among Malnourished Children with Environmental Enteric Dysfunction in a Multi-Country Cohort Study

The Environmental Enteric Dysfunction Biopsy Initiative Consortium offers a unique opportunity to assess the relationships of biomarkers collected across multiple geographic regions with the histopathology of the disease tissue target.  Specifically, the authors aimed to identify whether four biomarkers were associated with individual histologic features of environmental enteric dysfunction as well as with an environmental enteric dysfunction summary index score.  The four biomarkers included three common fecal markers of intestinal inflammation (e.g., myeloperoxidase, calprotectin and neopterin) as well as a dual sugar permeability test.  According to the findings, these “four commonly used markers of enteric dysfunction were associated with specific histologic features.”  While acknowledging the challenges of obtaining relevant tissue, the authors believe “these findings form the basis for further environmental enteric dysfunction biomarker validation research.”

Enteric Pathogens’ Relationship with Small Bowel Histological Features of Environmental Enteric Dysfunction in a Multi-Country Cohort Study

This study sought to determine if fecal enteropathogen carriage predicts small bowel histopathology across three geographically distinct pediatric cohorts using a standardized and validated environmental enteric dysfunction histology scoring system.  Findings suggested that “detection of some enteropathogens in asymptomatic infections was associated with subsequent environmental enteric dysfunction histopathology.”  Specifically, 97% of the children under study had at least one enteropathogen detected, including 95%, 48%, and 45% with a bacteria, protozoa or virus, respectively.  While it is not possible to directly compare carriage prevalence to other studies due to different platform content, the prevalence in this study was similar to other studies.  In short, “these novel findings offer a basis for future environmental enteric dysfunction etiology and pathogenesis studies.”

While recent research has provided clues to unravelling the complex pathogenesis of environmental enteric dysfunction and suggested possible strategies for managing this condition, effective diagnostic methods as well as potential therapeutic targets remain elusive.  According to the editorial accompanying this supplement, Environmental Enteropathy: An Old Clinical Conundrum with New Diagnostic and Therapeutic Opportunities, “the many results outlined in this supplement can help point the way to additional research pathways to address environmental enteric dysfunction as well as to mitigate its impact on critical public health issues, such as growth faltering, low efficacy of oral vaccines, and poor neurocognitive development.”