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1. Malnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial

Author

Chandwe, Kanta, Bwakura-Dangarembizi, Mutsa, Amadi, Beatrice, Tawodzera, Gertrude, Ngosa, Deophine, Dzikiti, Anesu, Chulu, Nivea, Makuyana, Robert, Zyambo, Kanekwa, Mutasa, Kuda, Mulenga, Chola, Besa, Ellen, Sturgeon, Jonathan P., Mudzingwa, Shepherd, Simunyola, Bwalya, Kazhila, Lydia, Zyambo, Masuzyo, Sonkwe, Hazel, Mutasa, Batsirai, Chipunza, Miyoba, Sauramba, Virginia, Langhaug, Lisa, Mudenda, Victor, Murch, Simon H., Hill, Susan, Playford, Raymond J., VanBuskirk, Kelley, Prendergast, Andrew J., and Kelly, Paul

Published
2024
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2. Multiplexed immunohistochemical evaluation of small bowel inflammatory and epithelial parameters in environmental enteric dysfunction

Author

Ahmed, Kumail, Ahmed, Sheraz, Alam, Md Ashraful, Das, Subhasish, Denson, Lee A, Fahim, Shah Mohammad, Gazi, Md Amran, Haberman, Yael, Hasan, Md Mehedi, Hossain, Md Shabab, Hotwani, Aneeta, Iqbal, Junaid, Iqbal, Najeeha Talat, Jakhro, Sadaf, Kabir, Furqan, Liu, Ta-Chiang, Mann, Barbara J, Marie, Chelsea, Mazumder, Ramendra Nath, Mudenda, Victor, Mulenga, Chola, Qureshi, Abdul Khalique, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Tearney, Guillermo J, Umrani, Fayaz, Yilmaz, Omer H, VanBuskirk, Kelley, Mweetwa, Monica, Kolterman, Tad, Raghavan, Shyam, Ahmed, Tahmeed, Ali, S Asad, Nahar Begum, SM Khodeza, Besa, Ellen, Denno, Donna M, Jamil, Zehra, Kelly, Paul, Mahfuz, Mustafa, Moore, Sean R, Mouksassi, Samer, Petri, William A, Jr., Tarr, Phillip I, Sullivan, Peter B, and Moskaluk, Christopher A

Published
2024
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3. Biomarker relationships with small bowel histopathology among malnourished children with environmental enteric dysfunction in a multicountry cohort study

Author

Ahmed, Kumail, Ahmed, Sheraz, Ahmed, Tahmeed, Alam, Md. Ashraful, Amadi, Beatrice, Begum, S.M. Khodeza Nahar, Besa, Ellen, Fahim, Shah Mohammad, Gazi, Md. Amran, Gilchrist, Carol A., Haque, Rashidul, Hasan, Md. Mehedi, Hossain, Md. Shabab, Hotwani, Aneeta, Hussain, Shahneel, Iqbal, Junaid, Jakhro, Sadaf, Kabir, Furqan, Liu, Ta-Chiang, Mann, Barbara J., Mazumder, Ramendra Nath, Memon, Waheeda, Moskaluk, Christopher A, Qureshi, Abdul Khalique, Ragahavan, Shyam S, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Sarker, Shafiqul Alam, Sullivan, Peter B, Tearney, Guillermo J., Umrani, Fayaz, Yilmaz, Omer H., Zyambo, Kanekwa, Mahfuz, Mustafa, Coomes, David, Abdalla, Marwa, Mweetwa, Monica, VanBuskirk, Kelley, Iqbal, Najeeha T, Ali, S Asad, Chandwe, Kanta, Das, Subhasish, Kelly, Paul, Shaikh, Nurmohammad, Tarr, Phillip I, and Denno, Donna M

Published
2024
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4. Histopathology underlying environmental enteric dysfunction in a cohort study of undernourished children in Bangladesh, Pakistan, and Zambia compared with United States children

Author

Ahmed, Kumail, Ahmed, Sheraz, Alam, Md. Ashraful, Begum, S.M. Khodeza Nahar, Besa, Ellen, Chandwe, Kanta, Chipunza, Miyoba, Das, Subhasish, Denson, Lee A., Fahim, Shah Mohammad, Gazi, Md. Amran, Hasan, Md. Mehedi, Hotwani, Aneeta, Iqbal, Junaid, Iqbal, Najeeha Talat, Jakhro, Sadaf, Kabir, Furqan, Lawrence, Sarah, Mann, Barbara J., Mazumder, Ramendra Nath, Memon, Waheeda, Morgan, Brooks, Mudenda, Victor, Mulenga, Chola, Mweetwa, Monica, Qureshi, Abdul Khalique, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Sarker, Shafiqul Alam, Umrani, Fayaz, Zyambo, Kanekwa, Kelly, Paul, VanBuskirk, Kelley, Coomes, David, Mouksassi, Samer, Smith, Gerald, Jamil, Zehra, Hossain, Md Shabab, Syed, Sana, Marie, Chelsea, Tarr, Phillip I, Sullivan, Peter B, Petri, William A, Jr, Denno, Donna M, Ahmed, Tahmeed, Mahfuz, Mustafa, Ali, S Asad, Moore, Sean R, Ndao, I Malick, Tearney, Guillermo J, Ömer H Yilmaz, Raghavan, Shyam S, Moskaluk, Christopher A, and Liu, Ta-Chiang

Published
2024
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5. Duodenal transcriptomics demonstrates signatures of tissue inflammation and immune cell infiltration in children with environmental enteric dysfunction across global centers

Author

Ahmed, Kumail, Ahmed, Sheraz, Alam, Md Ashraful, Auble, David, Begum, SM Khodeza Nahar, Besa, Ellen, Chama, Mubanga, Denno, Donna M, Fahim, Shah Mohammad, Gazi, Md Amran, Haberman, Yael, Haque, Rashidul, Hasan, Md Mehedi, Hossain, Md Shabab, Hotwani, Aneeta, Iqbal, Najeeha Talat, Jan, Ning-Jiun, Kabir, Furqan, Kumar, Pankaj, Liu, Ta-Chiang, Mann, Barbara J, Mazumder, Ramendra Nath, Mohammad, Anwaruddin, Moskaluk, Christopher A, Nayak, Uma, Ndao, Malick, Ragahavan, Shyam S, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Sarker, Shafiqul Alam, Shaikh, Nurmohammad, Sullivan, Peter B, Tearney, Guillermo J, Umrani, Fayaz, Yilmaz, Omer H, Zyambo, Kanekwa, Marie, Chelsea, Das, Subhasish, Coomes, David, Ahmed, Tahmeed, Ali, S Asad, Iqbal, Junaid, Kelly, Paul, Mahfuz, Mustafa, Moore, Sean R, Petri, William A, Jr., Tarr, Phillip I, and Denson, Lee A

Published
2024
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8. Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition

Author

Sturgeon, Jonathan P., primary, Tome, Joice, additional, Dumbura, Cherlynn, additional, Majo, Florence D., additional, Ngosa, Deophine, additional, Mutasa, Kuda, additional, Zyambo, Kanekwa, additional, Besa, Ellen, additional, Chandwe, Kanta, additional, Kapoma, Chanda, additional, Mwapenya, Benjamin, additional, Nathoo, Kusum J., additional, Bourke, Claire D., additional, Ntozini, Robert, additional, Chasekwa, Bernard, additional, Smuk, Melanie, additional, Bwakura-Dangarembizi, Mutsa, additional, Amadi, Beatrice, additional, Kelly, Paul, additional, and Prendergast, Andrew J., additional

Published
2024
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12. Multiplexed immunohistochemical evaluation of small bowel inflammatory and epithelial parameters in environmental enteric dysfunction

Author

VanBuskirk, Kelley, Mweetwa, Monica, Kolterman, Tad, Raghavan, Shyam, Ahmed, Tahmeed, Ali, S Asad, Nahar Begum, SM Khodeza, Besa, Ellen, Denno, Donna M, Jamil, Zehra, Kelly, Paul, Mahfuz, Mustafa, Moore, Sean R, Mouksassi, Samer, Petri, William A, Tarr, Phillip I, Sullivan, Peter B, Moskaluk, Christopher A, Ahmed, Kumail, Ahmed, Sheraz, Alam, Md Ashraful, Das, Subhasish, Denson, Lee A, Fahim, Shah Mohammad, Gazi, Md Amran, Haberman, Yael, Hasan, Md Mehedi, Hossain, Md Shabab, Hotwani, Aneeta, Iqbal, Junaid, Iqbal, Najeeha Talat, Jakhro, Sadaf, Kabir, Furqan, Liu, Ta-Chiang, Mann, Barbara J, Marie, Chelsea, Mazumder, Ramendra Nath, Mudenda, Victor, Mulenga, Chola, Qureshi, Abdul Khalique, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Tearney, Guillermo J, Umrani, Fayaz, and Yilmaz, Omer H

Abstract

Environmental enteric dysfunction (EED) is characterized by reduced absorptive capacity and barrier function of the small intestine, leading to poor ponderal and linear childhood growth.

Published
2024
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13. Biomarker relationships with small bowel histopathology among malnourished children with environmental enteric dysfunction in a multicountry cohort study

Author

Mahfuz, Mustafa, Coomes, David, Abdalla, Marwa, Mweetwa, Monica, VanBuskirk, Kelley, Iqbal, Najeeha T, Ali, S Asad, Chandwe, Kanta, Das, Subhasish, Kelly, Paul, Shaikh, Nurmohammad, Tarr, Phillip I, Denno, Donna M, Ahmed, Kumail, Ahmed, Sheraz, Ahmed, Tahmeed, Alam, Md. Ashraful, Amadi, Beatrice, Begum, S.M. Khodeza Nahar, Besa, Ellen, Fahim, Shah Mohammad, Gazi, Md. Amran, Gilchrist, Carol A., Haque, Rashidul, Hasan, Md. Mehedi, Hossain, Md. Shabab, Hotwani, Aneeta, Hussain, Shahneel, Iqbal, Junaid, Jakhro, Sadaf, Kabir, Furqan, Liu, Ta-Chiang, Mann, Barbara J., Mazumder, Ramendra Nath, Memon, Waheeda, Moskaluk, Christopher A, Qureshi, Abdul Khalique, Ragahavan, Shyam S, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Sarker, Shafiqul Alam, Sullivan, Peter B, Tearney, Guillermo J., Umrani, Fayaz, Yilmaz, Omer H., and Zyambo, Kanekwa

Abstract

Validated biomarkers could catalyze environmental enteric dysfunction (EED) research.

Published
2024
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14. Histopathology underlying environmental enteric dysfunction in a cohort study of undernourished children in Bangladesh, Pakistan, and Zambia compared with United States children

Author

Kelly, Paul, VanBuskirk, Kelley, Coomes, David, Mouksassi, Samer, Smith, Gerald, Jamil, Zehra, Hossain, Md Shabab, Syed, Sana, Marie, Chelsea, Tarr, Phillip I, Sullivan, Peter B, Petri, William A, Denno, Donna M, Ahmed, Tahmeed, Mahfuz, Mustafa, Ali, S Asad, Moore, Sean R, Ndao, I Malick, Tearney, Guillermo J, Yilmaz, Ömer H, Raghavan, Shyam S, Moskaluk, Christopher A, Liu, Ta-Chiang, Ahmed, Kumail, Ahmed, Sheraz, Alam, Md. Ashraful, Begum, S.M. Khodeza Nahar, Besa, Ellen, Chandwe, Kanta, Chipunza, Miyoba, Das, Subhasish, Denson, Lee A., Fahim, Shah Mohammad, Gazi, Md. Amran, Hasan, Md. Mehedi, Hotwani, Aneeta, Iqbal, Junaid, Iqbal, Najeeha Talat, Jakhro, Sadaf, Kabir, Furqan, Lawrence, Sarah, Mann, Barbara J., Mazumder, Ramendra Nath, Memon, Waheeda, Morgan, Brooks, Mudenda, Victor, Mulenga, Chola, Mweetwa, Monica, Qureshi, Abdul Khalique, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Sarker, Shafiqul Alam, Umrani, Fayaz, and Zyambo, Kanekwa

Abstract

Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder associated with growth impairment, delayed neurocognitive development, and impaired oral vaccine responses.

Published
2024
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15. Duodenal transcriptomics demonstrates signatures of tissue inflammation and immune cell infiltration in children with environmental enteric dysfunction across global centers

Author

Marie, Chelsea, Das, Subhasish, Coomes, David, Ahmed, Tahmeed, Ali, S Asad, Iqbal, Junaid, Kelly, Paul, Mahfuz, Mustafa, Moore, Sean R, Petri, William A, Tarr, Phillip I, Denson, Lee A, Ahmed, Kumail, Ahmed, Sheraz, Alam, Md Ashraful, Auble, David, Begum, SM Khodeza Nahar, Besa, Ellen, Chama, Mubanga, Denno, Donna M, Fahim, Shah Mohammad, Gazi, Md Amran, Haberman, Yael, Haque, Rashidul, Hasan, Md Mehedi, Hossain, Md Shabab, Hotwani, Aneeta, Iqbal, Najeeha Talat, Jan, Ning-Jiun, Kabir, Furqan, Kumar, Pankaj, Liu, Ta-Chiang, Mann, Barbara J, Mazumder, Ramendra Nath, Mohammad, Anwaruddin, Moskaluk, Christopher A, Nayak, Uma, Ndao, Malick, Ragahavan, Shyam S, Rahman, Masudur, Rahman, Najeeb, Sadiq, Kamran, Sarker, Shafiqul Alam, Shaikh, Nurmohammad, Sullivan, Peter B, Tearney, Guillermo J, Umrani, Fayaz, Yilmaz, Omer H, and Zyambo, Kanekwa

Abstract

Environmental enteric dysfunction (EED) is an inflammatory condition of the small intestine that is prevalent in children residing in low- and middle-income countries. EED is accompanied by profound histopathologic changes in the small bowel, loss of absorptive capacity, increased intestinal permeability, increased microbial translocation, and nutrient loss.

Published
2024
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18. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation

Author

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, 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, 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, and Kelly, Paul

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.

Published
2023

19. Potential determinants of low circulating glucagon‐like peptide 2 concentrations in Zambian children with non‐responsive stunting

Author

Besa, Ellen, primary, Tembo, Mizinga Jacqueline, additional, Mulenga, Chola, additional, Mweetwa, Monica, additional, Choudhry, Naheed, additional, Chandwe, Kanta, additional, Storer, Chad, additional, Head, Richard, additional, Amadi, Beatrice, additional, Haritunians, Talin, additional, McGovern, Dermot, additional, Kwenda, Geoffrey, additional, Peiris, Madusha, additional, and Kelly, Paul, additional

Published
2023
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20. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation

Author

Kummerlowe, Conner, primary, Mwakamui, Simutanyi, additional, Hughes, Travis K., additional, Mulugeta, Nolawit, additional, Mudenda, Victor, additional, Besa, Ellen, additional, Zyambo, Kanekwa, additional, Shay, Jessica E. S., additional, Fleming, Ira, additional, Vukovic, Marko, additional, Doran, Ben A., additional, Aicher, Toby P., additional, Wadsworth, Marc H., additional, Bramante, Juliet Tongue, additional, Uchida, Amiko M., additional, Fardoos, Rabiah, additional, Asowata, Osaretin E., additional, Herbert, Nicholas, additional, Yilmaz, Ömer H., additional, Kløverpris, Henrik N., additional, Garber, John J., additional, Ordovas-Montañes, José, additional, Gartner, Zev J., additional, Wallach, Thomas, additional, Shalek, Alex K., additional, and Kelly, Paul, additional

Published
2022
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21. 13C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults

Author

Schillinger, Robert J., Mwakamui, Simutanyi, Mulenga, Chola, Tembo, Mizinga, Hodges, Phoebe, Besa, Ellen, Chandwe, Kanta, Owino, Victor O., Edwards, Christine A., Kelly, Paul, and Morrison, Douglas J.

Subjects
General Medicine
Abstract

ObjectivesEnvironmental enteropathy (EE) is a subclinical disorder highly prevalent in tropical and disadvantaged populations and is thought to play a role in growth faltering in children, poor responses to oral vaccines, and micronutrient deficiencies. This study aims to evaluate the potential of a non-invasive breath test based on stable isotopes for evaluation of impaired digestion and absorption of sucrose in EE.MethodsWe optimized a 13C-sucrose breath test (13C-SBT) in 19 young adults in Glasgow, United Kingdom. In a further experiment (in 18 adults) we validated the 13C-SBT using Reducose, an intestinal glucosidase inhibitor. We then compared the 13C-SBT to intestinal mucosal morphometry, immunostaining for sucrose-isomaltase (SI) expression, and SI activity in 24 Zambian adults with EE.ResultsFully labeled sucrose (0.3 mg/kg) provided clear breath enrichment signals over 2–3 h in both British and Zambian adults, more than fivefold higher than naturally enriched sucrose. Reducose dramatically impaired 13C-sucrose digestion, reducing 4 h 13CO2 breath recovery by > 50%. Duodenal biopsies in Zambian adults confirmed the presence of EE, and SI immunostaining was present in 16/24 adults. The kinetics of 13CO2 evolution were consistently faster in participants with detectable SI immunostaining. Although sucrase activity was strongly correlated with villus height (r = 0.72; P < 0.05) after adjustment for age, sex and body mass index, there were no correlations between 13C-SBT and villus height or measured sucrase activity in pinch biopsies.ConclusionA 13C-SBT was developed which was easy to perform, generated clear enrichment of 13CO2 in breath samples, and clearly reports sucrase activity. Further work is needed to validate it and understand its applications in evaluating EE.

Published
2022

22. Level of Awareness, Acceptance, and Congruency with the Vision, Mission, Goals, and Program Outcomes of the College of Education of Capiz State University (CAPSU).

Author

Joaquin, Cleo Jude A., BESA, Ellen Mae D., and Joaquin, Hazel D.

Subjects
*ACCEPTANCE (Psychology), *EXPERIMENTAL design, *STAKEHOLDERS, *COMPUTER software, *STATE universities & colleges
Abstract

This research evaluated the level of awareness, acceptance, and congruence with the Vision, Mission, and Goals (VMGO) and Program Outcomes of the College of Education at Capiz State University (CAPSU). It adopted a mixed-method research design, utilizing a descriptive-quantitative approach, with both internal and external stakeholders of CAPSU as the primary data source. Through a survey questionnaire employing a five-point Likert scale, this study measures stakeholders' awareness, acceptability, and congruence with CapSU's VMG and the program outcomes of the College of Education. The gathered data were analyzed using weighted mean, T-test, and Pearson Correlation via SPSS software (version 20). Findings suggest a high level of awareness and acceptance of CAPSU's VMGO among internal and external stakeholders, and a high congruence between the VMGO and actual educational practices. Interestingly, external stakeholders showed moderate acceptance of the College of Education's program outcomes. No significant difference was found between internal and external stakeholders' levels of awareness and acceptance, nor any correlation among these variables. The study concludes by highlighting the necessity for continuous efforts to enhance stakeholders' awareness, acceptance, and congruence with the VMGO and program outcomes. Additionally, it emphasizes the importance of stakeholder involvement in any revision process related to the VMGO. Lastly, the study recommends periodic assessments of stakeholders' awareness and acceptance of the VMG for sustainable institutional development. [ABSTRACT FROM AUTHOR]

Published
2023
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24. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation

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, 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., and Kelly, Paul

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.

Published
2022

25. Publisher Correction: Adaptation of the small intestine to microbial enteropathogens in Zambian children with stunting

Author

Amadi, Beatrice, primary, Zyambo, Kanekwa, additional, Chandwe, Kanta, additional, Besa, Ellen, additional, Mulenga, Chola, additional, Mwakamui, Simutanyi, additional, Siyumbwa, Stepfanie, additional, Croft, Sophie, additional, Banda, Rose, additional, Chipunza, Miyoba, additional, Chifunda, Kapula, additional, Kazhila, Lydia, additional, VanBuskirk, Kelley, additional, and Kelly, Paul, additional

Published
2021
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27. Single-cell profiling of environmental enteropathy reveals signatures of epithelial remodeling and immune activation in severe disease

Author

Kummerlowe, Conner, primary, Wallach, Thomas, additional, Mwakamui, Simutanyi, additional, Hughes, Travis K., additional, Mulugeta, Nolawit, additional, Mudenda, Victor, additional, Besa, Ellen, additional, Zyambo, Kanekwa, additional, Fleming, Ira, additional, Vukovic, Marko, additional, Doran, Ben A., additional, Bramante, Juliet Tongue, additional, Uchida, Amiko M., additional, Garber, John J., additional, Ordovas-Montanes, Jose, additional, Gartner, Zev, additional, Shalek, Alex K., additional, and Kelly, Paul, additional

Published
2021
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30. Impaired Barrier Function and Autoantibody Generation in Malnutrition Enteropathy in Zambia

Author

Amadi, Beatrice, Besa, Ellen, Zyambo, Kanekwa, Kaonga, Patrick, Louis-Auguste, John, Chandwe, Kanta, Tarr, Phillip I., Denno, Donna M., Nataro, James P., Faubion, William, Sailer, Anne, Yeruva, Sunil, Brantner, Tricia, Murray, Joseph, Prendergast, Andrew J., Turner, Jerrold R., and Kelly, Paul

Subjects
Diarrhea, Lipopolysaccharides, Male, Biopsy, lcsh:Medicine, Environmental enteric dysfunction, Endoscopy, Gastrointestinal, Antigens, CD, Humans, Claudin-4, Child, Glucagon-like peptide 2, Autoantibodies, lcsh:R5-920, Severe Acute Malnutrition, Malnutrition, lcsh:R, HIV, Cadherins, Intestines, Cross-Sectional Studies, Child, Preschool, Tissue transglutaminase serology, deamidated gliadin peptide serology, Commentary, Female, lcsh:Medicine (General), Biomarkers, Enteropathy, Microbial translocation, Research Paper
Abstract

Intestinal damage in malnutrition constitutes a threat to the survival of many thousands of children globally. We studied children in Lusaka, Zambia, with severe acute malnutrition (SAM) and persistent diarrhea using endoscopy, biopsy and analysis of markers and protective proteins in blood and intestinal secretions. We carried out parallel investigations in apparently healthy adults, and analyzed biomarkers only in apparently healthy children. Villus height and crypt depth did not differ in children with SAM and adult controls, but epithelial surface was reduced in children with SAM (median 445, interquartile range (IQR) 388, 562 μm per 100 μm muscularis mucosae) compared to adults (578, IQR 465,709; P = 0.004). Histological lesions and disruptions of claudin-4 and E-cadherin were most pronounced in children with SAM. Circulating lipopolysaccharide, a marker of bacterial translocation, was higher in malnourished children (251, IQR 110,460 EU/ml) than in healthy children (51, IQR 0,111; P = 0.0001). Other translocation markers showed similar patterns. Anti-Deamidated Gliadin Peptide IgG concentrations, although within the normal range, were higher in children with SAM (median 2.7 U/ml, IQR 1.5–8.6) than in adults (1.6, 1.4–2.1; P = 0.005), and were inversely correlated with villus height (ρ = − 0.79, n = 13, P = 0.001). Malnutrition enteropathy is associated with intestinal barrier failure and immune dysregulation., Highlights • Enteropathy in children with severe acute malnutrition is characterized by variable villus blunting and epithelial disruption. • Biomarkers indicate very high levels of microbial translocation from intestinal lumen to systemic circulation. • Coeliac-type autoantibodies were associated with villus blunting, microbial translocation markers and mortality. There is abundant evidence that childhood malnutrition is a major contributor to mortality in many low and middle income countries. Mortality remains unacceptably high. Here we show that severe acute malnutrition was characterized by very high levels of microbial translocation and inflammation, and severe mucosal damage with disturbed tight junction protein expression. Antibodies to tissue transglutaminase and deamidated gliadin peptides, although within the normal range, correlated with villus morphology, translocation markers and death. Malnutrition enteropathy permits mucosal inflammation, microbial translocation and immune dysregulation.

Published
2017

31. Direct Biomarkers of Microbial Translocation Correlate with Immune Activation in Adult Zambians with Environmental Enteropathy and Hepatosplenic Schistosomiasis

Author

Kaonga, Patrick, Kaimoyo, Evans, Besa, Ellen, Zyambo, Kanekwa, Sinkala, Edford, and Kelly, Paul

Subjects
Adult, DNA, Bacterial, Lipopolysaccharides, Male, Lipoproteins, Gene Dosage, Zambia, Articles, Middle Aged, Real-Time Polymerase Chain Reaction, Host-Parasite Interactions, Teichoic Acids, Intestinal Diseases, Mice, Young Adult, Cross-Sectional Studies, RAW 264.7 Cells, Bacterial Translocation, RNA, Ribosomal, 16S, Animals, Cytokines, Humans, Schistosomiasis, Female, Biomarkers
Abstract

Microbial translocation is a poorly understood consequence of several disorders such as environmental enteropathy (EE) and hepatosplenic schistosomiasis (HSS). Herein, we compared biomarkers of microbial origin and immune activation in adults with these disorders and in healthy controls. A cross-sectional study was conducted in participants with EE recruited from Misisi compound, Lusaka, Zambia; HSS patients and healthy controls from the University Teaching Hospital, Lusaka. Plasma lipopolysaccharides (LPSs) was measured by limulus amoebocyte lysate assay, plasma 16S ribosomal RNA (16S rRNA) gene copy number was quantified by quantitative real-time polymerase chain reaction, Toll-like receptor ligand (TLRL) activity by QUANTI-Blue detection medium, and cytokines from cell culture supernatant by Cytometric Bead Array. In univariate analysis LPS, 16S rRNA gene copy number, and TLR activity were all high and correlated with each other and with cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10, and IL-4 secreted by the RAW-Blue cells. After controlling for baseline characteristic, biomarkers of microbial translocation in blood were predictors of TNF-α, IL-6, and IL-10 activation in cell culture supernatant from EE participants and HSS patients but not in healthy controls. TLR activity showed the strongest correlation with TNF-α. These data provide correlative evidence that microbial translocation contributes to systemic cytokine activation in two disorders common in the tropics, with total TLR ligand estimation showing the strongest correlation with TNF-α (r = 0.66, P < 0.001).

Published
2017

32. Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition (HOPE-SAM): rationale and methods of a longitudinal observational study

Author

Bwakura-Dangarembizi, Mutsa, primary, Amadi, Beatrice, additional, Bourke, Claire D, additional, Robertson, Ruairi C, additional, Mwapenya, Benjamin, additional, Chandwe, Kanta, additional, Kapoma, Chanda, additional, Chifunda, Kapula, additional, Majo, Florence, additional, Ngosa, Deophine, additional, Chakara, Pamela, additional, Chulu, Nivea, additional, Masimba, Faithfull, additional, Mapurisa, Idah, additional, Besa, Ellen, additional, Mutasa, Kuda, additional, Mwakamui, Simutanyi, additional, Runodamoto, Thompson, additional, Humphrey, Jean H, additional, Ntozini, Robert, additional, Wells, Jonathan C K, additional, Manges, Amee R, additional, Swann, Jonathan R, additional, Walker, A Sarah, additional, Nathoo, Kusum J, additional, Kelly, Paul, additional, and Prendergast, Andrew J, additional

Published
2019
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33. Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines

Author

Mwanza-Lisulo, Mpala, primary, Chomba, Mumba S., additional, Chama, Mubanga, additional, Besa, Ellen C., additional, Funjika, Evelyn, additional, Zyambo, Kanekwa, additional, Banda, Rose, additional, Imikendu, Mercy, additional, Sianongo, Sandie, additional, Hancock, Robert E.W., additional, Lee, Amy, additional, Chilengi, Roma, additional, Stagg, Andy J., additional, Namangala, Boniface, additional, and Kelly, Paul M., additional

Published
2018
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34. Rifaximin Reduces Markers of Inflammation and Bacterial 16S rRNA in Zambian Adults with Hepatosplenic Schistosomiasis: A Randomized Control Trial

Author

Sinkala, Edford, primary, Zyambo, Kanekwa, additional, Besa, Ellen, additional, Kaonga, Patrick, additional, Nsokolo, Bright, additional, Kayamba, Violet, additional, Vinikoor, Michael, additional, Zulu, Rabison, additional, Bwalya, Martin, additional, Foster, Graham R., additional, and Kelly, Paul, additional

Published
2018
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35. Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea

Author

Farràs, Marta, primary, Chandwe, Kanta, additional, Mayneris-Perxachs, Jordi, additional, Amadi, Beatrice, additional, Louis-Auguste, John, additional, Besa, Ellen, additional, Zyambo, Kanekwa, additional, Guerrant, Richard, additional, Kelly, Paul, additional, and Swann, Jonathan Richard, additional

Published
2018
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42. Therapeutic interventions targeting enteropathy in severe acute malnutrition modulate systemic and vascular inflammation and epithelial regeneration.

Author

Sturgeon JP, Mutasa K, Bwakura-Dangarembizi M, Amadi B, Ngosa D, Dzikiti A, Chandwe K, Besa E, Mutasa B, Murch SH, Hill S, Playford RJ, VanBuskirk K, Kelly P, and Prendergast AJ

Abstract

Background: Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition, and children hospitalised with complications have unacceptably high mortality. Complicated SAM is a multisystem disease characterised pathophysiologically by muscle wasting, systemic inflammation, metabolic dysfunction, and malnutrition enteropathy including epithelial barrier dysfunction. There is a clear need for novel interventions to address the underlying pathogenic perturbations of complicated SAM., Methods: In this analysis of tertiary outcomes from a phase II multi-centre trial in Zambia and Zimbabwe, multiplex biomarkers were measured in 122 children (57% male) with SAM randomised following stabilisation ('baseline') to one of four interventions for 14 days to treat malnutrition enteropathy: budesonide, N-acetylglucosamine, colostrum, or teduglutide, compared with standard-of-care. Following measurement of 35 biomarkers from day 15 plasma samples using Luminex and ELISA, the dimensionality of biomarker data was reduced using principal component analysis., Findings: Both budesonide and colostrum reduced systemic inflammation (as measured by CD14, IL1-ra, CRP, and LBP), while children receiving colostrum had higher GLP2 and angiopoietin, and lower circulating lipopolysaccharide, suggesting better restoration of epithelial barrier function. N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF)., Interpretation: Interventions aimed at ameliorating malnutrition enteropathy showed plausible effects on biomarkers of inflammation and epithelial regeneration, demonstrating an interdependence of systemic inflammation and enteropathy markers seen in structural analysis. Given the interplay between inflammation and tissue restoration in malnutrition, this mechanism of action supports larger trials to determine the clinical benefits of interventions, either alone or in combination, in children with complicated SAM., Funding: This analysis of tertiary outcomes for the TAME trial was funded by a Wellcome grant to JPS (220566/Z/20/Z). The TAME trial was funded by a grant from the Medical Research Council (UK), number MR/P024033/1. AJP is funded by Wellcome (108065/Z/15/Z). Takeda UK provided teduglutide at a discounted price., Competing Interests: Declaration of interests RJP was previously an external consultant to Colostrum UK which provided the bovine colostrum used in these studies. RJP has also been an external consultant to Sterling Technology (USA) and an employee of Pantheryx Inc (USA) who produce and distribute bovine colostrum. There was no bovine colostrum company involvement in the production of this article or editing of its content. SH has had funding for teduglutide studies and lectured and participated in advisory boards on behalf of Takeda., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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43. 13 C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults.

Author

Schillinger RJ, Mwakamui S, Mulenga C, Tembo M, Hodges P, Besa E, Chandwe K, Owino VO, Edwards CA, Kelly P, and Morrison DJ

Abstract

Objectives: Environmental enteropathy (EE) is a subclinical disorder highly prevalent in tropical and disadvantaged populations and is thought to play a role in growth faltering in children, poor responses to oral vaccines, and micronutrient deficiencies. This study aims to evaluate the potential of a non-invasive breath test based on stable isotopes for evaluation of impaired digestion and absorption of sucrose in EE., Methods: We optimized a 13 C-sucrose breath test ( 13 C-SBT) in 19 young adults in Glasgow, United Kingdom. In a further experiment (in 18 adults) we validated the 13 C-SBT using Reducose, an intestinal glucosidase inhibitor. We then compared the 13 C-SBT to intestinal mucosal morphometry, immunostaining for sucrose-isomaltase (SI) expression, and SI activity in 24 Zambian adults with EE., Results: Fully labeled sucrose (0.3 mg/kg) provided clear breath enrichment signals over 2-3 h in both British and Zambian adults, more than fivefold higher than naturally enriched sucrose. Reducose dramatically impaired 13 C-sucrose digestion, reducing 4 h 13 CO 2 breath recovery by > 50%. Duodenal biopsies in Zambian adults confirmed the presence of EE, and SI immunostaining was present in 16/24 adults. The kinetics of 13 CO 2 evolution were consistently faster in participants with detectable SI immunostaining. Although sucrase activity was strongly correlated with villus height ( r = 0.72; P < 0.05) after adjustment for age, sex and body mass index, there were no correlations between 13 C-SBT and villus height or measured sucrase activity in pinch biopsies., Conclusion: A 13 C-SBT was developed which was easy to perform, generated clear enrichment of 13 CO 2 in breath samples, and clearly reports sucrase activity. Further work is needed to validate it and understand its applications in evaluating EE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schillinger, Mwakamui, Mulenga, Tembo, Hodges, Besa, Chandwe, Owino, Edwards, Kelly and Morrison.)

Published
2022
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