EBioMedicine (Apr 2017)
Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study
- Margaret N. Kosek,
- Tahmeed Ahmed,
- Zulfiquar Bhutta,
- Laura Caulfield,
- Richard Guerrant,
- Eric Houpt,
- Gagandeep Kang,
- Margaret Kosek,
- Gwenyth Lee,
- Aldo Lima,
- Benjamin J.J. McCormick,
- James Platts-Mills,
- Jessica Seidman,
- Laura Caulfield,
- Margaret Kosek,
- Gwenyth Lee,
- Benjamin J.J. McCormick,
- Jessica Seidman,
- Rebecca R. Blank,
- Michael Gottlieb,
- Stacey L. Knobler,
- Dennis R. Lang,
- Mark A. Miller,
- Karen H. Tountas,
- Zulfiqar A. Bhutta,
- Laura Caulfield,
- William Checkley,
- Richard L. Guerrant,
- Eric Houpt,
- Margaret N. Kosek,
- Dennis R. Lang,
- Carl J. Mason,
- Mark A. Miller,
- Laura E. Murray-Kolb,
- William A. Petri, Jr.,
- Jessica C. Seidman,
- Tahmeed Ahmed,
- Pascal Bessong,
- Zulfiqar A. Bhutta,
- Rashidul Haque,
- Sushil John,
- Gagandeep Kang,
- Margaret N. Kosek,
- Aldo A.M. Lima,
- Estomih R. Mduma,
- Reinaldo B. Oriá,
- Prakash Sunder Shrestha,
- Sanjaya Kumar Shrestha,
- Erling Svensen,
- Anita K.M. Zaidi,
- Cláudia B. Abreu,
- Angel Mendez Acosta,
- Imran Ahmed,
- A.M. Shamsir Ahmed,
- Asad Ali,
- Ramya Ambikapathi,
- Leah Barrett,
- Aubrey Bauck,
- Eliwaza Bayyo,
- Ladaporn Bodhidatta,
- Anuradha Bose,
- J. Daniel Carreon,
- Ram Krishna Chandyo,
- Vivek Charu,
- Hilda Costa,
- Rebecca Dillingham,
- Alessandra Di Moura,
- Viyada Doan,
- Jose Quirino Filho,
- Jhanelle Graham,
- Christel Hoest,
- Iqbal Hossain,
- Munirul Islam,
- M. Steffi Jennifer,
- Shiny Kaki,
- Beena Koshy,
- Gwenyth Lee,
- Álvaro M. Leite,
- Noélia L. Lima,
- Bruna L.L. Maciel,
- Mustafa Mahfuz,
- Cloupas Mahopo,
- Angelina Maphula,
- Benjamin J.J. McCormick,
- Monica McGrath,
- Archana Mohale,
- Milena Moraes,
- Francisco S. Mota,
- Jayaprakash Muliyil,
- Regisiana Mvungi,
- Gaurvika Nayyar,
- Emanuel Nyathi,
- Maribel Paredes Olortegui,
- Reinaldo Oria,
- Angel Orbe Vasquez,
- William K. Pan,
- John Pascal,
- Crystal L. Patil,
- Laura Pendergast,
- Silvia Rengifo Pinedo,
- James Platts-Mills,
- Stephanie Psaki,
- Mohan Venkata Raghava,
- Karthikeyan Ramanujam,
- Muneera Rasheed,
- Zeba A. Rasmussen,
- Stephanie A. Richard,
- Anuradha Rose,
- Reeba Roshan,
- Barbara Schaefer,
- Rebecca Scharf,
- Jessica C. Seidman,
- Srujan L. Sharma,
- Binob Shrestha,
- Rita Shrestha,
- Suzanne Simons,
- Alberto M. Soares,
- Rosa M.S. Mota,
- Sajid Soofi,
- Tor Strand,
- Fahmida Tofail,
- Rahul J. Thomas,
- Ali Turab,
- Manjeswori Ulak,
- Vivian Wang,
- Ladislaus Yarrot,
- Pablo Peñataro Yori,
- Didar Alam,
- Ramya Ambikapathi,
- Caroline Amour,
- Cesar Banda Chavez,
- Sudhir Babji,
- Rosa Rios de Burga,
- Viyada Doan,
- Julian Torres Flores,
- Jean Gratz,
- Ajila T. George,
- Dinesh Hariraju,
- Alexandre Havt,
- Eric Houpt,
- Priyadarshani Karunakaran,
- Robin P. Lazarus,
- Ila F. Lima,
- Monica McGrath,
- Dinesh Mondal,
- Pedro H.Q.S. Medeiros,
- Rosemary Nshama,
- Josiane Quetz,
- Shahida Qureshi,
- Sophy Raju,
- Anup Ramachandran,
- Rakhi Ramadas,
- A. Catharine Ross,
- Mery Siguas Salas,
- Amidou Samie,
- Kerry Schulze,
- Jessica C. Seidman,
- E. Shanmuga Sundaram,
- Buliga Mujaga Swema,
- Dixner Rengifo Trigoso
Affiliations
- Margaret N. Kosek
- Tahmeed Ahmed
- Zulfiquar Bhutta
- Laura Caulfield
- Richard Guerrant
- Eric Houpt
- Gagandeep Kang
- Margaret Kosek
- Gwenyth Lee
- Aldo Lima
- Benjamin J.J. McCormick
- James Platts-Mills
- Jessica Seidman
- Laura Caulfield
- Margaret Kosek
- Gwenyth Lee
- Benjamin J.J. McCormick
- Jessica Seidman
- Rebecca R. Blank
- Foundation for the NIH, Bethesda, MD, USA
- Michael Gottlieb
- Foundation for the NIH, Bethesda, MD, USA
- Stacey L. Knobler
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Dennis R. Lang
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Mark A. Miller
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Karen H. Tountas
- Foundation for the NIH, Bethesda, MD, USA
- Zulfiqar A. Bhutta
- Aga Khan University, Karachi, Pakistan
- Laura Caulfield
- Johns Hopkins University, Baltimore, MD, USA
- William Checkley
- Johns Hopkins University, Baltimore, MD, USA
- Richard L. Guerrant
- University of Virginia, Charlottesville, VA, USA
- Eric Houpt
- University of Virginia, Charlottesville, VA, USA
- Margaret N. Kosek
- Johns Hopkins University, Baltimore, MD, USA
- Dennis R. Lang
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Carl J. Mason
- Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
- Mark A. Miller
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Laura E. Murray-Kolb
- The Pennsylvania State University, University Park, PA, USA
- William A. Petri, Jr.
- University of Virginia, Charlottesville, VA, USA
- Jessica C. Seidman
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Tahmeed Ahmed
- icddr, b, Dhaka, Bangladesh
- Pascal Bessong
- University of Venda, Thohoyandou, South Africa
- Zulfiqar A. Bhutta
- Aga Khan University, Karachi, Pakistan
- Rashidul Haque
- icddr, b, Dhaka, Bangladesh
- Sushil John
- Christian Medical College, Vellore, India
- Gagandeep Kang
- Christian Medical College, Vellore, India
- Margaret N. Kosek
- Johns Hopkins University, Baltimore, MD, USA
- Aldo A.M. Lima
- Universidade Federal do Ceara, Fortaleza, Brazil
- Estomih R. Mduma
- Haydom Lutheran Hospital, Haydom, Tanzania
- Reinaldo B. Oriá
- Universidade Federal do Ceara, Fortaleza, Brazil
- Prakash Sunder Shrestha
- Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
- Sanjaya Kumar Shrestha
- Walter Reed/AFRIMS Research Unit, Kathmandu, Nepal
- Erling Svensen
- Haukeland University Hospital, Bergen, Norway
- Anita K.M. Zaidi
- Aga Khan University, Karachi, Pakistan
- Cláudia B. Abreu
- Universidade Federal do Ceara, Fortaleza, Brazil
- Angel Mendez Acosta
- A.B. PRISMA, Iquitos, Peru
- Imran Ahmed
- Aga Khan University, Karachi, Pakistan
- A.M. Shamsir Ahmed
- icddr, b, Dhaka, Bangladesh
- Asad Ali
- Aga Khan University, Karachi, Pakistan
- Ramya Ambikapathi
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Leah Barrett
- University of Virginia, Charlottesville, VA, USA
- Aubrey Bauck
- Johns Hopkins University, Baltimore, MD, USA
- Eliwaza Bayyo
- Haydom Lutheran Hospital, Haydom, Tanzania
- Ladaporn Bodhidatta
- Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
- Anuradha Bose
- Christian Medical College, Vellore, India
- J. Daniel Carreon
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Ram Krishna Chandyo
- Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
- Vivek Charu
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Hilda Costa
- Universidade Federal do Ceara, Fortaleza, Brazil
- Rebecca Dillingham
- University of Virginia, Charlottesville, VA, USA
- Alessandra Di Moura
- Universidade Federal do Ceara, Fortaleza, Brazil
- Viyada Doan
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Jose Quirino Filho
- Universidade Federal do Ceara, Fortaleza, Brazil
- Jhanelle Graham
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Christel Hoest
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Iqbal Hossain
- icddr, b, Dhaka, Bangladesh
- Munirul Islam
- icddr, b, Dhaka, Bangladesh
- M. Steffi Jennifer
- Christian Medical College, Vellore, India
- Shiny Kaki
- Christian Medical College, Vellore, India
- Beena Koshy
- Christian Medical College, Vellore, India
- Gwenyth Lee
- Johns Hopkins University, Baltimore, MD, USA
- Álvaro M. Leite
- Universidade Federal do Ceara, Fortaleza, Brazil
- Noélia L. Lima
- Universidade Federal do Ceara, Fortaleza, Brazil
- Bruna L.L. Maciel
- Universidade Federal do Ceara, Fortaleza, Brazil
- Mustafa Mahfuz
- icddr, b, Dhaka, Bangladesh
- Cloupas Mahopo
- University of Venda, Thohoyandou, South Africa
- Angelina Maphula
- University of Venda, Thohoyandou, South Africa
- Benjamin J.J. McCormick
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Monica McGrath
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Archana Mohale
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Milena Moraes
- Universidade Federal do Ceara, Fortaleza, Brazil
- Francisco S. Mota
- Universidade Federal do Ceara, Fortaleza, Brazil
- Jayaprakash Muliyil
- Christian Medical College, Vellore, India
- Regisiana Mvungi
- Haydom Lutheran Hospital, Haydom, Tanzania
- Gaurvika Nayyar
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Emanuel Nyathi
- University of Venda, Thohoyandou, South Africa
- Maribel Paredes Olortegui
- A.B. PRISMA, Iquitos, Peru
- Reinaldo Oria
- Universidade Federal do Ceara, Fortaleza, Brazil
- Angel Orbe Vasquez
- A.B. PRISMA, Iquitos, Peru
- William K. Pan
- Duke University, Durham, NC, USA
- John Pascal
- Haydom Lutheran Hospital, Haydom, Tanzania
- Crystal L. Patil
- University of Illinois at Chicago, IL, USA
- Laura Pendergast
- Temple University, Philadelphia, PA, USA
- Silvia Rengifo Pinedo
- A.B. PRISMA, Iquitos, Peru
- James Platts-Mills
- University of Virginia, Charlottesville, VA, USA
- Stephanie Psaki
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Mohan Venkata Raghava
- Christian Medical College, Vellore, India
- Karthikeyan Ramanujam
- Christian Medical College, Vellore, India
- Muneera Rasheed
- Aga Khan University, Karachi, Pakistan
- Zeba A. Rasmussen
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Stephanie A. Richard
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Anuradha Rose
- Christian Medical College, Vellore, India
- Reeba Roshan
- Christian Medical College, Vellore, India
- Barbara Schaefer
- The Pennsylvania State University, University Park, PA, USA
- Rebecca Scharf
- University of Virginia, Charlottesville, VA, USA
- Jessica C. Seidman
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Srujan L. Sharma
- Christian Medical College, Vellore, India
- Binob Shrestha
- Walter Reed/AFRIMS Research Unit, Kathmandu, Nepal
- Rita Shrestha
- Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
- Suzanne Simons
- The Pennsylvania State University, University Park, PA, USA
- Alberto M. Soares
- Universidade Federal do Ceara, Fortaleza, Brazil
- Rosa M.S. Mota
- Universidade Federal do Ceara, Fortaleza, Brazil
- Sajid Soofi
- Aga Khan University, Karachi, Pakistan
- Tor Strand
- Walter Reed/AFRIMS Research Unit, Kathmandu, Nepal
- Fahmida Tofail
- icddr, b, Dhaka, Bangladesh
- Rahul J. Thomas
- Christian Medical College, Vellore, India
- Ali Turab
- Aga Khan University, Karachi, Pakistan
- Manjeswori Ulak
- Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
- Vivian Wang
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Ladislaus Yarrot
- Haydom Lutheran Hospital, Haydom, Tanzania
- Pablo Peñataro Yori
- Johns Hopkins University, Baltimore, MD, USA
- Didar Alam
- Aga Khan University, Karachi, Pakistan
- Ramya Ambikapathi
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Caroline Amour
- Haydom Lutheran Hospital, Haydom, Tanzania
- Cesar Banda Chavez
- A.B. PRISMA, Iquitos, Peru
- Sudhir Babji
- Christian Medical College, Vellore, India
- Rosa Rios de Burga
- A.B. PRISMA, Iquitos, Peru
- Viyada Doan
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Julian Torres Flores
- A.B. PRISMA, Iquitos, Peru
- Jean Gratz
- University of Virginia, Charlottesville, VA, USA
- Ajila T. George
- Christian Medical College, Vellore, India
- Dinesh Hariraju
- Christian Medical College, Vellore, India
- Alexandre Havt
- Universidade Federal do Ceara, Fortaleza, Brazil
- Eric Houpt
- University of Virginia, Charlottesville, VA, USA
- Priyadarshani Karunakaran
- Christian Medical College, Vellore, India
- Robin P. Lazarus
- Christian Medical College, Vellore, India
- Ila F. Lima
- Universidade Federal do Ceara, Fortaleza, Brazil
- Monica McGrath
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- Dinesh Mondal
- icddr, b, Dhaka, Bangladesh
- Pedro H.Q.S. Medeiros
- Universidade Federal do Ceara, Fortaleza, Brazil
- Rosemary Nshama
- Haydom Lutheran Hospital, Haydom, Tanzania
- Josiane Quetz
- Universidade Federal do Ceara, Fortaleza, Brazil
- Shahida Qureshi
- Aga Khan University, Karachi, Pakistan
- Sophy Raju
- Christian Medical College, Vellore, India
- Anup Ramachandran
- Christian Medical College, Vellore, India
- Rakhi Ramadas
- Christian Medical College, Vellore, India
- A. Catharine Ross
- The Pennsylvania State University, University Park, PA, USA
- Mery Siguas Salas
- A.B. PRISMA, Iquitos, Peru
- Amidou Samie
- University of Venda, Thohoyandou, South Africa
- Kerry Schulze
- Johns Hopkins University, Baltimore, MD, USA
- Jessica C. Seidman
- Fogarty International Center/National Institutes of Health, Bethesda, MD, USA
- E. Shanmuga Sundaram
- Christian Medical College, Vellore, India
- Buliga Mujaga Swema
- Haydom Lutheran Hospital, Haydom, Tanzania
- Dixner Rengifo Trigoso
- A.B. PRISMA, Iquitos, Peru
- DOI
- https://doi.org/10.1016/j.ebiom.2017.02.024
- Journal volume & issue
-
Vol. 18,
no. C
pp. 109 – 117
Abstract
Background: Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods: Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings: Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation: The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation. Funding: Bill & Melinda Gates Foundation.
Keywords
