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

Author

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, Rebecca R. Blank, Michael Gottlieb, Stacey L. Knobler, Dennis R. Lang, Mark A. Miller, Karen H. Tountas, Zulfiqar A. Bhutta, William Checkley, Richard L. Guerrant, Carl J. Mason, Laura E. Murray-Kolb, William A. Petri, Jr., Jessica C. Seidman, Pascal Bessong, Rashidul Haque, Sushil John, 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, Álvaro M. Leite, Noélia L. Lima, Bruna L.L. Maciel, Mustafa Mahfuz, Cloupas Mahopo, Angelina Maphula, 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, Stephanie Psaki, Mohan Venkata Raghava, Karthikeyan Ramanujam, Muneera Rasheed, Zeba A. Rasmussen, Stephanie A. Richard, Anuradha Rose, Reeba Roshan, Barbara Schaefer, Rebecca Scharf, 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, Caroline Amour, Cesar Banda Chavez, Sudhir Babji, Rosa Rios de Burga, Julian Torres Flores, Jean Gratz, Ajila T. George, Dinesh Hariraju, Alexandre Havt, Priyadarshani Karunakaran, Robin P. Lazarus, Ila F. Lima, 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, E. Shanmuga Sundaram, Buliga Mujaga Swema, and Dixner Rengifo Trigoso

Subjects
Enteropathy, Undernutrition, Stunting, Enteropathogen, Child growth, Child health, Medicine, Medicine (General), R5-920
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.

Published
2017
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2. Use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the MAL-ED cohort study

Author

James A Platts-Mills, MD, Jie Liu, PhD, Elizabeth T Rogawski, PhD, Furqan Kabir, MSc, Paphavee Lertsethtakarn, PhD, Mery Siguas, BSc, Shaila S Khan, MSc, Ira Praharaj, MD, Arinao Murei, BSc, Rosemary Nshama, BSc, Buliga Mujaga, BSc, Alexandre Havt, PhD, Irene A Maciel, PhD, Timothy L McMurry, PhD, Darwin J Operario, PhD, Mami Taniuchi, PhD, Jean Gratz, MS, Suzanne E Stroup, MS, James H Roberts, Adil Kalam, MSc, Fatima Aziz, MSc, Shahida Qureshi, MSc, M Ohedul Islam, MSc, Pimmada Sakpaisal, MSc, Sasikorn Silapong, B BSc, Pablo P Yori, MPH, Revathi Rajendiran, MSc, Blossom Benny, MSc, Monica McGrath, ScD, Benjamin J J McCormick, DPhil, Jessica C Seidman, PhD, Dennis Lang, PhD, Michael Gottlieb, PhD, Richard L Guerrant, MD, Aldo A M Lima, ProfPhD, Jose Paulo Leite, PhD, Amidou Samie, PhD, Pascal O Bessong, ProfPhD, Nicola Page, PhD, Ladaporn Bodhidatta, MD, Carl Mason, MD, Sanjaya Shrestha, MD, Ireen Kiwelu, PhD, Estomih R Mduma, MPH, Najeeha T Iqbal, PhD, Zulfiqar A Bhutta, ProfPhD, Tahmeed Ahmed, ProfMBBS, Rashidul Haque, PhD, Gagandeep Kang, ProfMD, Margaret N Kosek, MD, Eric R Houpt, ProfMD, Angel Mendez Acosta, Rosa Rios de Burga, Cesar Banda Chavez, Julian Torres Flores, Maribel Paredes Olotegui, Silvia Rengifo Pinedo, Dixner Rengifo Trigoso, Angel Orbe Vasquez, Imran Ahmed, Didar Alam, Asad Ali, Muneera Rasheed, Sajid Soofi, Ali Turab, Aisha Yousafzai, Anita KM Zaidi, Binob Shrestha, Bishnu Bahadur Rayamajhi, Tor Strand, Geetha Ammu, Sudhir Babji, Anuradha Bose, Ajila T George, Dinesh Hariraju, M. Steffi Jennifer, Sushil John, Shiny Kaki, Priyadarshani Karunakaran, Beena Koshy, Robin P Lazarus, Jayaprakash Muliyil, Preethi Ragasudha, Mohan Venkata Raghava, Sophy Raju, Anup Ramachandran, Rakhi Ramadas, Karthikeyan Ramanujam, Anuradha Rose, Reeba Roshan, Srujan L Sharma, Shanmuga Sundaram, Rahul J Thomas, William K Pan, Ramya Ambikapathi, J Daniel Carreon, Viyada Doan, Christel Hoest, Stacey Knobler, Mark A Miller, Stephanie Psaki, Zeba Rasmussen, Stephanie A Richard, Karen H Tountas, Erling Svensen, Caroline Amour, Eliwaza Bayyo, Regisiana Mvungi, John Pascal, Ladislaus Yarrot, Leah Barrett, Rebecca Dillingham, William A Petri, Rebecca Scharf, AM Shamsir Ahmed, Md Ashraful Alam, Umma Haque, Md Iqbal Hossain, Munirul Islam, Mustafa Mahfuz, Dinesh Mondal, Baitun Nahar, Fahmida Tofail, Ram Krishna Chandyo, Prakash Sunder Shrestha, Rita Shrestha, Manjeswori Ulak, Aubrey Bauck, Robert Black, Laura Caulfield, William Checkley, Gwenyth Lee, Kerry Schulze, Samuel Scott, Laura E Murray-Kolb, A Catharine Ross, Barbara Schaefer, Suzanne Simons, Laura Pendergast, Cláudia B Abreu, Hilda Costa, Alessandra Di Moura, José Quirino Filho, Álvaro M Leite, Noélia L Lima, Ila F Lima, Bruna LL Maciel, Pedro HQS Medeiros, Milena Moraes, Francisco S Mota, Reinaldo B Oriá, Josiane Quetz, Alberto M Soares, Rosa MS Mota, Crystal L Patil, Cloupas Mahopo, Angelina Maphula, and Emanuel Nyathi

Subjects
Public aspects of medicine, RA1-1270
Abstract

Summary: Background: Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods: We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings: We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation: Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding: Bill & Melinda Gates Foundation.

Published
2018
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3. Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study

Author

Elizabeth T Rogawski, PhD, Jie Liu, PhD, James A Platts-Mills, MD, Furqan Kabir, MSc, Paphavee Lertsethtakarn, PhD, Mery Siguas, BSc, Shaila S Khan, MSc, Ira Praharaj, MD, Arinao Murei, BSc, Rosemary Nshama, BSc, Buliga Mujaga, BSc, Alexandre Havt, PhD, Irene A Maciel, PhD, Darwin J Operario, PhD, Mami Taniuchi, PhD, Jean Gratz, MS, Suzanne E Stroup, MS, James H Roberts, Adil Kalam, MSc, Fatima Aziz, MSc, Shahida Qureshi, MSc, M Ohedul Islam, MSc, Pimmada Sakpaisal, MSc, Sasikorn Silapong, MSc, Pablo P Yori, MPH, Revathi Rajendiran, MSc, Blossom Benny, MSc, Monica McGrath, ScD, Jessica C Seidman, PhD, Dennis Lang, PhD, Michael Gottlieb, PhD, Richard L Guerrant, MD, Aldo A M Lima, ProfPhD, Jose Paulo Leite, PhD, Amidou Samie, PhD, Pascal O Bessong, ProfPhD, Nicola Page, PhD, Ladaporn Bodhidatta, MD, Carl Mason, MD, Sanjaya Shrestha, MD, Ireen Kiwelu, PhD, Estomih R Mduma, MPH, Najeeha T Iqbal, PhD, Zulfiqar A Bhutta, ProfPhD, Tahmeed Ahmed, ProfMBBS, Rashidul Haque, PhD, Gagandeep Kang, ProfMD, Margaret N Kosek, MD, Eric R Houpt, ProfMD, Angel Mendez Acosta, Rosa Rios de Burga, Cesar Banda Chavez, Julian Torres Flores, Maribel Paredes Olotegui, Silvia Rengifo Pinedo, Dixner Rengifo Trigoso, Angel Orbe Vasquez, Imran Ahmed, Didar Alam, Asad Ali, Muneera Rasheed, Sajid Soofi, Ali Turab, Aisha Yousafzai, Anita KM Zaidi, Binob Shrestha, Bishnu Bahadur Rayamajhi, Tor Strand, Geetha Ammu, Sudhir Babji, Anuradha Bose, Ajila T George, Dinesh Hariraju, M. Steffi Jennifer, Sushil John, Shiny Kaki, Priyadarshani Karunakaran, Beena Koshy, Robin P Lazarus, Jayaprakash Muliyil, Preethi Ragasudha, Mohan Venkata Raghava, Sophy Raju, Anup Ramachandran, Rakhi Ramadas, Karthikeyan Ramanujam, Anuradha Rose, Reeba Roshan, Srujan L Sharma, Shanmuga Sundaram, Rahul J Thomas, William K Pan, Ramya Ambikapathi, J Daniel Carreon, Viyada Doan, Christel Hoest, Stacey Knobler, Mark A Miller, Stephanie Psaki, Zeba Rasmussen, Stephanie A Richard, Karen H Tountas, Erling Svensen, Caroline Amour, Eliwaza Bayyo, Regisiana Mvungi, John Pascal, Ladislaus Yarrot, Leah Barrett, Rebecca Dillingham, William A Petri, Rebecca Scharf, AM Shamsir Ahmed, Md Ashraful Alam, Umma Haque, Md Iqbal Hossain, Munirul Islam, Mustafa Mahfuz, Dinesh Mondal, Baitun Nahar, Fahmida Tofail, Ram Krishna Chandyo, Prakash Sunder Shrestha, Rita Shrestha, Manjeswori Ulak, Aubrey Bauck, Robert Black, Laura Caulfield, William Checkley, Gwenyth Lee, Kerry Schulze, Samuel Scott, Laura E Murray-Kolb, A Catharine Ross, Barbara Schaefer, Suzanne Simons, Laura Pendergast, Cláudia B Abreu, Hilda Costa, Alessandra Di Moura, José Quirino Filho, Álvaro M Leite, Noélia L Lima, Ila F Lima, Bruna LL Maciel, Pedro HQS Medeiros, Milena Moraes, Francisco S Mota, Reinaldo B Oriá, Josiane Quetz, Alberto M Soares, Rosa MS Mota, Crystal L Patil, Cloupas Mahopo, Angelina Maphula, and Emanuel Nyathi

Subjects
Public aspects of medicine, RA1-1270
Abstract

Summary: Background: Enteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings. Methods: We used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding. Findings: Among 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites. Interpretation: Subclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Funding: Bill & Melinda Gates Foundation.

Published
2018
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4. Intestinal permeability and inflammation mediate the association between nutrient density of complementary foods and biochemical measures of micronutrient status in young children: results from the MAL-ED study

Author

Erling Svensen, Gagandeep Kang, Dixner Rengifo Trigoso, M Munirul Islam, Benjamin J.J. McCormick, Ramya Ambikapathi, Sophy Raju, Rita Shrestha, Cláudia B. Abreu, Ram Krishna Chandyo, Maribel Paredes Olotegui, Gaurvika M. L. Nayyar, Archana Mohale, Margaret Kosek, Rebecca Blank, Álvaro M. Leite, Srujan Lam Sharma, Manjeswori Ulak, Richard L. Guerrant, Anup Ramachandran, Robin P. Lazarus, Josiane da Silva Quetz, AM Shamsir Ahmed, Estomih R. Mduma, Binob Shrestha, Anita K. M. Zaidi, Aubrey Bauck, Cesar Banda Chavez, Regisiana Mvungi, Silvia Rengifo Pinedo, Sanjaya K. Shrestha, Jean Gratz, Sudhir Babji, Priyadarshani Karunakaran, Pablo Peñataro Yori, José Q. Filho, Laura E. Murray-Kolb, Rosa Maria Salani Mota, Stephanie A. Richard, Ajila T. George, Sajid Bashir Soofi, Vivek Charu, Rosemary Nshama, Zeba A Rasmussen, M. Steffi Jennifer, Rahul J. Thomas, Ladislaus Blacy Yarrot, Alberto M. Soares, Noélia L. Lima, Laura L. Pendergast, Milena Lima de Moraes, Ila F. N. Lima, A. Catharine Ross, Eric R. Houpt, Ladaporn Bodhidatta, Laura E. Caulfield, Estomih Mduma, Tahmeed Ahmed, Jayaprakash Muliyil, Mery Siguas Salas, Rebecca Dillingham, Shahida Qureshi, Sushil John, Caroline Amour, Francisco Suetônio Bastos Mota, Pedro H. Q. S. Medeiros, Angel Mendez Acosta, Iqbal Hossain, Eliwaza Bayyo, Dinesh Mondal, Imran Ahmed, Buliga Mujaga Swema, H. Costa, Michael Gottlieb, Beena Koshy, Mark A. Miller, Vivian Ota Wang, Jhanelle Graham, Muneera A. Rasheed, Alexandre Havt, Bruna Leal Lima Maciel, Cloupas Mahopo, Anuradha Bose, Prakash S. Shrestha, Jessica C. Seidman, Monica McGrath, Alessandra Di Moura, Ali Turab, Viyada Doan, William Pan, Pascal O. Bessong, Didar Alam, Rakhi Ramadas, Tor A. Strand, Reinaldo B. Oriá, Stephanie Psaki, Karthikeyan Ramanujam, John M. Pascal, Rosa Burga, Amidou Samie, William A. Petri, Dinesh Hariraju, Dennis Lang, Christel Hoest, Robert E. Black, Karen H. Tountas, Mohan Venkata Raghava, Angel Orbe Vasquez, Zulfiqar A Bhutta, Emanuel Nyathi, Julian Torres Flores, Rashidul Haque, Leah J. Barrett, J. Daniel Carreon, Carl J. Mason, Zulfiqar A. Bhutta, Stacey Knobler, Rebecca J. Scharf, Suzanne Simons, Kerry Schulze, Crystal L. Patil, Aldo A. M. Lima, Reeba Roshan, Angelina Maphula, Maribel Paredes Olortegui, James A Platts-Mills, Fahmida Tofail, Shiny Kaki, Asad Ali, Gwenyth O. Lee, Sanjaya K. Shrestra, Mustafa Mahfuz, Shanmuga Sundaram, William Checkley, and Barbara A. Schaefer

Subjects
medicine.medical_specialty, Micronutrient deficiency, Anemia, 030231 tropical medicine, Nutritional Status, Medicine (miscellaneous), Lower risk, Systemic inflammation, Permeability, intestinal barrier function, Cohort Studies, Nutrient density, Feces, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Micronutrients, 030212 general & internal medicine, Infant Nutritional Physiological Phenomena, Inflammation, Nutrition and Dietetics, biology, business.industry, International Nutrition, Infant, Bayes Theorem, Nutrients, medicine.disease, Micronutrient, environmental enteropathy, Intestines, micronutrient status, Ferritin, Intestinal Diseases, Original Research Communications, Malnutrition, Endocrinology, biology.protein, Infant Food, medicine.symptom, diet, business, Biomarkers
Abstract

Background Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation. Objective We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status. Methods Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network. Results A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations. Conclusions EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

Published
2019
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