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EBioMedicine. 2017 Apr;18:109-117. doi: 10.1016/j.ebiom.2017.02.024. Epub 2017 Mar 8.

Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study.

Collaborators (159)

Ahmed T, Bhutta Z, Caulfield L, Guerrant R, Houpt E, Kang G, Kosek M, Lee G, Lima A, McCormick BJJ, Platts-Mills J, Seidman J, Caulfield L, Kosek M, Lee G, McCormick BJJ, Seidman J, Blank RR1, Gottlieb M2, Knobler SL3, Lang DR4, Miller MA5, Tountas KH6, Bhutta ZA7, Caulfield L8, Checkley W9, Guerrant RL10, Houpt E11, Kosek MN12, Lang DR4, Mason CJ13, Miller MA5, Murray-Kolb LE14, Petri WA Jr15, Seidman JC16, Ahmed T17, Bessong P18, Bhutta ZA7, Haque R19, John S20, Kang G21, Kosek MN12, Lima AAM22, Mduma ER23, Oriá RB24, Shrestha PS25, Shrestha SK26, Svensen E27, Zaidi AKM28, Abreu CB29, Acosta AM30, Ahmed I31, Shamsir Ahmed AM32, Ali A33, Ambikapathi R34, Barrett L35, Bauck A36, Bayyo E37, Bodhidatta L38, Bose A39, Daniel Carreon J40, Chandyo RK41, Charu V42, Costa H43, Dillingham R44, Di Moura A45, Doan V46, Filho JQ47, Graham J48, Hoest C49, Hossain I50, Islam M51, Steffi Jennifer M52, Kaki S53, Koshy B54, Lee G55, Leite ÁM56, Lima NL57, Maciel BLL58, Mahfuz M59, Mahopo C60, Maphula A61, McCormick BJJ62, McGrath M63, Mohale A64, Moraes M65, Mota FS66, Muliyil J67, Mvungi R68, Nayyar G69, Nyathi E70, Olortegui MP71, Oria R24, Vasquez AO72, Pan WK73, Pascal J74, Patil CL75, Pendergast L76, Pinedo SR77, Platts-Mills J78, Psaki S79, Raghava MV80, Ramanujam K81, Rasheed M82, Rasmussen ZA83, Richard SA84, Rose A85, Roshan R86, Schaefer B87, Scharf R88, Seidman JC16, Sharma SL89, Shrestha B90, Shrestha R91, Simons S92, Soares AM93, Mota RMS94, Soofi S95, Strand T96, Tofail F97, Thomas RJ98, Turab A99, Ulak M100, Wang V101, Yarrot L102, Yori PP103, Alam D104, Ambikapathi R34, Amour C105, Chavez CB106, Babji S107, de Burga RR108, Doan V46, Flores JT109, Gratz J110, George AT111, Hariraju D112, Havt A113, Houpt E11, Karunakaran P114, Lazarus RP115, Lima IF116, McGrath M63, Mondal D117, Medeiros PHQS118, Nshama R119, Quetz J120, Qureshi S121, Raju S122, Ramachandran A123, Ramadas R124, Catharine Ross A125, Salas MS126, Samie A127, Schulze K128, Seidman JC16, Shanmuga Sundaram E129, Swema BM130, Trigoso DR131.

Author information

1
Foundation for the NIH, Bethesda, MD, USA. Electronic address: rebecca.blank@gmail.com.
2
Foundation for the NIH, Bethesda, MD, USA. Electronic address: mgottlieb@fnih.org.
3
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: Stacey.Knobler@nih.gov.
4
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA; Foundation for the NIH, Bethesda, MD, USA. Electronic address: Lang4@fnih.org.
5
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: Mark.Miller3@nih.gov.
6
Foundation for the NIH, Bethesda, MD, USA. Electronic address: ktountas@fnih.org.
7
Aga Khan University, Karachi, Pakistan. Electronic address: zulfiqar.bhutta@aku.edu.
8
Johns Hopkins University, Baltimore, MD, USA. Electronic address: lcaulfi1@jhu.edu.
9
Johns Hopkins University, Baltimore, MD, USA; Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: wcheckl1@jhmi.edu.
10
University of Virginia, Charlottesville, VA, USA. Electronic address: guerrant@virginia.edu.
11
University of Virginia, Charlottesville, VA, USA. Electronic address: erh6k@virginia.edu.
12
Johns Hopkins University, Baltimore, MD, USA. Electronic address: mkosek@jhmi.edu.
13
Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. Electronic address: carlmason@icloud.com.
14
The Pennsylvania State University, University Park, PA, USA. Electronic address: lem118@psu.edu.
15
University of Virginia, Charlottesville, VA, USA. Electronic address: wap3g@virginia.edu.
16
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: Jessica.Seidman@nih.gov.
17
icddr, b, Dhaka, Bangladesh. Electronic address: tahmeed@icddrb.org.
18
University of Venda, Thohoyandou, South Africa. Electronic address: pascal.bessong@univen.ac.za.
19
icddr, b, Dhaka, Bangladesh. Electronic address: rhaque@icddrb.org.
20
Christian Medical College, Vellore, India. Electronic address: rikkisush@cmcvellore.ac.in.
21
Christian Medical College, Vellore, India. Electronic address: gkang@cmcvellore.ac.in.
22
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: alima@ufc.br.
23
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: estomih.mduma@haydom.co.tz.
24
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: rbo5u@hscmail.mcc.virginia.edu.
25
Institute of Medicine, Tribhuvan University, Kathmandu, Nepal. Electronic address: prakashsunder@hotmail.com.
26
Walter Reed/AFRIMS Research Unit, Kathmandu, Nepal. Electronic address: ShresthaSK@afrims.org.
27
Haukeland University Hospital, Bergen, Norway; Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: Erling.Svensen@cih.uib.no.
28
Aga Khan University, Karachi, Pakistan. Electronic address: anita.zaidi@aku.edu.
29
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: claudia_beghini2004@yahoo.com.br.
30
A.B. PRISMA, Iquitos, Peru. Electronic address: amendez@prisma.org.pe.
31
Aga Khan University, Karachi, Pakistan. Electronic address: imran.ahmed@aku.edu.
32
icddr, b, Dhaka, Bangladesh. Electronic address: a.ahmed@uq.net.au.
33
Aga Khan University, Karachi, Pakistan. Electronic address: asad.ali@aku.edu.
34
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: rambikapathi@gmail.com.
35
University of Virginia, Charlottesville, VA, USA. Electronic address: ljbarrett@mindspring.com.
36
Johns Hopkins University, Baltimore, MD, USA. Electronic address: abauck1@jhu.edu.
37
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: elb.bayo@gmail.com.
38
Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. Electronic address: ladapornb@afrims.org.
39
Christian Medical College, Vellore, India. Electronic address: abose@cmcvellore.ac.in.
40
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: carreonj@mail.nih.gov.
41
Institute of Medicine, Tribhuvan University, Kathmandu, Nepal. Electronic address: ram.chandyo@uib.no.
42
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: vcharu@jhsph.edu.
43
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: hildacosta@hotmail.com.
44
University of Virginia, Charlottesville, VA, USA. Electronic address: rd8v@virginia.edu.
45
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: ferrer.alessandra@yahoo.com.br.
46
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: Viyada.Doan@nih.gov.
47
Universidade Federal do Ceara, Fortaleza, Brazil; Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: jqf_ce@yahoo.com.br.
48
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: jhalexia@gmail.com.
49
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: christel.host@nih.gov.
50
icddr, b, Dhaka, Bangladesh. Electronic address: ihossain@icddrb.org.
51
icddr, b, Dhaka, Bangladesh. Electronic address: mislam@icddrb.org.
52
Christian Medical College, Vellore, India. Electronic address: stefjeni.11@gmail.com.
53
Christian Medical College, Vellore, India. Electronic address: shinykaki@gmail.com.
54
Christian Medical College, Vellore, India. Electronic address: beenakoshy(1)@rediffmail.com.
55
Johns Hopkins University, Baltimore, MD, USA. Electronic address: gwenyth.lee@gmail.com.
56
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: alvaromadeiro@yahoo.com.br.
57
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: noelialima30@yahoo.com.br.
58
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: brunalimamaciel@gmail.com.
59
icddr, b, Dhaka, Bangladesh. Electronic address: mustafa@icddrb.org.
60
University of Venda, Thohoyandou, South Africa. Electronic address: mahopotc@gmail.com.
61
University of Venda, Thohoyandou, South Africa. Electronic address: angelina.maphula@univen.ac.za.
62
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: ben.mccormick@gmail.com.
63
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: mcgrath.monica@gmail.com.
64
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: mohalea@mail.nih.gov.
65
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: milenamaia@hotmail.com.
66
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: sulivan.mota@iprede.org.br.
67
Christian Medical College, Vellore, India. Electronic address: jpmuliyil@gmail.com.
68
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: regisiana@yahoo.com.
69
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: gaurvika@gmail.com.
70
University of Venda, Thohoyandou, South Africa. Electronic address: Emanuel.Nyathi@univen.ac.za.
71
A.B. PRISMA, Iquitos, Peru. Electronic address: mparedeso@prisma.org.pe.
72
A.B. PRISMA, Iquitos, Peru. Electronic address: angel_orbe@hotmail.com.
73
Duke University, Durham, NC, USA; Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: william.pan@duke.edu.
74
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: johnagustinopaschal@gmail.com.
75
University of Illinois at Chicago, IL, USA. Electronic address: cpatil@uic.edu.
76
Temple University, Philadelphia, PA, USA. Electronic address: laura.pendergast@temple.edu.
77
A.B. PRISMA, Iquitos, Peru. Electronic address: siguase36@hotmail.com.
78
University of Virginia, Charlottesville, VA, USA. Electronic address: jp5t@hscmail.mcc.virginia.edu.
79
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: spsaki@popcouncil.org.
80
Christian Medical College, Vellore, India. Electronic address: venkat@cmcvellore.ac.in.
81
Christian Medical College, Vellore, India. Electronic address: karthikeyan05@yahoo.co.in.
82
Aga Khan University, Karachi, Pakistan. Electronic address: muneera.rasheed@aku.edu.
83
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: Zeba.Rasmussen@nih.gov.
84
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: Stephanie.Richard@nih.gov.
85
Christian Medical College, Vellore, India. Electronic address: anurose@cmcvellore.ac.in.
86
Christian Medical College, Vellore, India. Electronic address: reebageorge@hotmail.com.
87
The Pennsylvania State University, University Park, PA, USA; Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: bas19@psu.edu.
88
University of Virginia, Charlottesville, VA, USA. Electronic address: rebeccascharf@virginia.edu.
89
Christian Medical College, Vellore, India. Electronic address: srujan.sharma@gmail.com.
90
Walter Reed/AFRIMS Research Unit, Kathmandu, Nepal. Electronic address: binobs@afrims.org.
91
Institute of Medicine, Tribhuvan University, Kathmandu, Nepal. Electronic address: ritas_12@yahoo.com.
92
The Pennsylvania State University, University Park, PA, USA. Electronic address: sxs126@psu.edu.
93
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: soaresam@ufc.br.
94
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: rosa@dema.ufc.br.
95
Aga Khan University, Karachi, Pakistan. Electronic address: sajid.soofi@aku.edu.
96
Walter Reed/AFRIMS Research Unit, Kathmandu, Nepal; University of Bergen, Norway. Electronic address: Tors@me.com.
97
icddr, b, Dhaka, Bangladesh. Electronic address: ftofail@icddrb.org.
98
Christian Medical College, Vellore, India. Electronic address: rj_thomas99@yahoo.com.
99
Aga Khan University, Karachi, Pakistan. Electronic address: turab.ali@aku.edu.
100
Institute of Medicine, Tribhuvan University, Kathmandu, Nepal. Electronic address: manjeswori@gmail.com.
101
Fogarty International Center/National Institutes of Health, Bethesda, MD, USA. Electronic address: aijun.wang@nih.gov.
102
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: ladisblacy@yahoo.com.
103
Johns Hopkins University, Baltimore, MD, USA. Electronic address: pyori@jhsph.edu.
104
Aga Khan University, Karachi, Pakistan. Electronic address: didar.alam@aku.edu.
105
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: lyneamour@gmail.com.
106
A.B. PRISMA, Iquitos, Peru. Electronic address: cebchavez@yahoo.com.
107
Christian Medical College, Vellore, India. Electronic address: sudhirbabji@cmcvellore.ac.in.
108
A.B. PRISMA, Iquitos, Peru. Electronic address: rosaburga@gmail.com.
109
A.B. PRISMA, Iquitos, Peru. Electronic address: jflores@prisma.org.pe.
110
University of Virginia, Charlottesville, VA, USA. Electronic address: jean.gratz@gmail.com.
111
Christian Medical College, Vellore, India. Electronic address: agilatgeorge@gmail.com.
112
Christian Medical College, Vellore, India. Electronic address: dinesh85@gmail.com.
113
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: ahavtbinda@gmail.com.
114
Christian Medical College, Vellore, India. Electronic address: priyadarshinicmc15@gmail.com.
115
Christian Medical College, Vellore, India. Electronic address: robin.lazarus@gmail.com.
116
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: ilafarm@yahoo.com.br.
117
icddr, b, Dhaka, Bangladesh. Electronic address: din63d@icddrb.org.
118
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: phquintela@hotmail.com.
119
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: nshamarosemary@yahoo.com.
120
Universidade Federal do Ceara, Fortaleza, Brazil. Electronic address: jquetz@gmail.com.
121
Aga Khan University, Karachi, Pakistan. Electronic address: shahida.qureshi@aku.edu.
122
Christian Medical College, Vellore, India. Electronic address: sophyraju@gmail.com.
123
Christian Medical College, Vellore, India. Electronic address: anuprama@yahoo.co.uk.
124
Christian Medical College, Vellore, India. Electronic address: rakhi.ram9@gmail.com.
125
The Pennsylvania State University, University Park, PA, USA. Electronic address: Acr6@psu.edu.
126
A.B. PRISMA, Iquitos, Peru. Electronic address: msiguas@prisma.org.pe.
127
University of Venda, Thohoyandou, South Africa. Electronic address: samieamidou@yahoo.com.
128
Johns Hopkins University, Baltimore, MD, USA. Electronic address: kschulz1@jhu.edu.
129
Christian Medical College, Vellore, India. Electronic address: shanmugame@cmcvellore.ac.in.
130
Haydom Lutheran Hospital, Haydom, Tanzania. Electronic address: buligamujaga@yahoo.co.uk.
131
A.B. PRISMA, Iquitos, Peru. Electronic address: drengifo@prisma.org.pe.

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 0-2years 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:

Child growth; Child health; Enteropathogen; Enteropathy; Stunting; Undernutrition

PMID:
28396264
PMCID:
PMC5405169
DOI:
10.1016/j.ebiom.2017.02.024
[Indexed for MEDLINE]
Free PMC Article

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