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    Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation.

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    Author
    Kummerlowe, Conner
    Mwakamui, Simutanyi
    Hughes, Travis K
    Mulugeta, Nolawit
    Mudenda, Victor
    Besa, Ellen
    Zyambo, Kanekwa
    Shay, Jessica E S
    Fleming, Ira
    Vukovic, Marko
    Doran, Ben A
    Aicher, Toby P
    Wadsworth, Marc H
    Bramante, Juliet Tongue
    Uchida, Amiko M
    Fardoos, Rabiah
    Asowata, Osaretin E
    Herbert, Nicholas
    Yilmaz, Ömer H
    Kløverpris, Henrik N
    Garber, John J
    Ordovas-Montañes, José
    Gartner, Zev J
    Wallach, Thomas
    Shalek, Alex K
    Kelly, Paul
    Show allShow less
    Journal title
    Science translational medicine
    Date Published
    2022-08-31
    Publication Volume
    14
    Publication Issue
    660
    Publication Begin page
    eabi8633
    
    Metadata
    Show full item record
    URI
    http://hdl.handle.net/20.500.12648/7556
    Abstract
    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.
    Citation
    Kummerlowe C, Mwakamui S, Hughes TK, Mulugeta N, Mudenda V, Besa E, Zyambo K, Shay JES, Fleming I, Vukovic M, Doran BA, Aicher TP, Wadsworth MH 2nd, Bramante JT, Uchida AM, Fardoos R, Asowata OE, Herbert N, Yilmaz ÖH, Kløverpris HN, Garber JJ, Ordovas-Montañes J, Gartner ZJ, Wallach T, Shalek AK, Kelly P. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation. Sci Transl Med. 2022 Aug 31;14(660):eabi8633. doi: 10.1126/scitranslmed.abi8633. Epub 2022 Aug 31. PMID: 36044598.
    DOI
    10.1126/scitranslmed.abi8633
    ae974a485f413a2113503eed53cd6c53
    10.1126/scitranslmed.abi8633
    Scopus Count
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    Downstate College of Medicine

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