Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation
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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 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.
In: Science Translational Medicine, Vol. 14, No. 660, eabi8633, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation
AU - Kummerlowe, Conner
AU - Mwakamui, Simutanyi
AU - Hughes, Travis K.
AU - Mulugeta, Nolawit
AU - Mudenda, Victor
AU - Besa, Ellen
AU - Zyambo, Kanekwa
AU - Shay, Jessica E.S.
AU - Fleming, Ira
AU - Vukovic, Marko
AU - Doran, Ben A.
AU - Aicher, Toby P.
AU - Wadsworth, Marc H.
AU - Bramante, Juliet Tongue
AU - Uchida, Amiko M.
AU - Fardoos, Rabiah
AU - Asowata, Osaretin E.
AU - Herbert, Nicholas
AU - Yilmaz, Ömer H.
AU - Kløverpris, Henrik N.
AU - Garber, John J.
AU - Ordovas-Montañes, José
AU - Gartner, Zev J.
AU - Wallach, Thomas
AU - Shalek, Alex K.
AU - Kelly, Paul
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1126/scitranslmed.abi8633
DO - 10.1126/scitranslmed.abi8633
M3 - Journal article
C2 - 36044598
AN - SCOPUS:85137051626
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 660
M1 - eabi8633
ER -
ID: 320647060