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 N. Kosek, Gwenyth Lee, Benjamin J.J. McCormick, Jessica C. 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, 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

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. 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. 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. 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. Bill & Melinda Gates Foundation.