Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 660, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abi8633
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Funding
- Barts and the London Charity [G-000829]
- Bill & Melinda Gates Foundation [OPP1066118]
- NIH [5U24AI118672, DK007762, F30-AI143160-01A1, F32DK128872, R01DK126545, R01GM135462]
- HHMI Damon Runyon Cancer Research Foundation Fellowship [DRG-2274-16]
- AGA Research Foundation's AGA-Takeda Pharmaceuticals Research Scholar Award in IBD [AGA2020-13-01]
- HDDC Pilot and Feasibility [P30 DK034854]
- Wellcome Trust [202485/Z/16/Z, 201433/A/16/A]
- Searle Scholars Program
- Beckman Young Investigator Program
- Sloan Research Fellowship in Chemistry
- Ragon Institute of MGH, MIT, and Harvard
- Richard and Susan Smith Family Foundation
- Food Allergy Science Initiative
- Leona M. and Harry B. Helmsley Charitable Trust
- Pew Charitable Trusts Biomedical Scholars
- New York Stem Cell Foundation
- Wellcome Trust [202485/Z/16/Z, 201433/A/16/A] Funding Source: Wellcome Trust
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Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. This study used single-cell RNA sequencing to analyze the cellular and molecular correlates of EE. The results showed that the transcriptional signatures of EE may be driven by an increased abundance of surface mucosal cells and identified dysregulated signaling pathways and increased proinflammatory cytokine gene expression in EE epithelium.
Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells-a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention.
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