Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation
<jats:p>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 ha...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science (AAAS)
2023
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| Online Access: | https://hdl.handle.net/1721.1/148390 |
| _version_ | 1811089522533859328 |
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| author | Kummerlowe, Conner Mwakamui, Simutanyi Hughes, Travis K Mulugeta, Nolawit Mudenda, Victor Besa, Ellen Zyambo, Kanekwa Shay, Jessica ES 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 |
| author2 | Massachusetts Institute of Technology. Computational and Systems Biology Program |
| author_facet | Massachusetts Institute of Technology. Computational and Systems Biology Program Kummerlowe, Conner Mwakamui, Simutanyi Hughes, Travis K Mulugeta, Nolawit Mudenda, Victor Besa, Ellen Zyambo, Kanekwa Shay, Jessica ES 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 |
| author_sort | Kummerlowe, Conner |
| collection | MIT |
| description | <jats:p>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.</jats:p> |
| first_indexed | 2024-09-23T14:20:32Z |
| format | Article |
| id | mit-1721.1/148390 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:20:32Z |
| publishDate | 2023 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1483902024-03-20T19:20:56Z Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation Kummerlowe, Conner Mwakamui, Simutanyi Hughes, Travis K Mulugeta, Nolawit Mudenda, Victor Besa, Ellen Zyambo, Kanekwa Shay, Jessica ES 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 Massachusetts Institute of Technology. Computational and Systems Biology Program Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Ragon Institute of MGH, MIT and Harvard <jats:p>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.</jats:p> 2023-03-07T15:58:27Z 2023-03-07T15:58:27Z 2022 2023-03-07T15:47:05Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/148390 Kummerlowe, Conner, Mwakamui, Simutanyi, Hughes, Travis K, Mulugeta, Nolawit, Mudenda, Victor et al. 2022. "Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation." Science Translational Medicine, 14 (660). en 10.1126/SCITRANSLMED.ABI8633 Science Translational Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Kummerlowe, Conner Mwakamui, Simutanyi Hughes, Travis K Mulugeta, Nolawit Mudenda, Victor Besa, Ellen Zyambo, Kanekwa Shay, Jessica ES 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 Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| title | Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| title_full | Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| title_fullStr | Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| title_full_unstemmed | Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| title_short | Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| title_sort | single cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation |
| url | https://hdl.handle.net/1721.1/148390 |
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