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

      Kosek, MN; Ahmed, T; Bhutta, ZA; Caulfield, L; Guerrant, RL; Houpt, E; Kang, G; Lee, G; Lima, AAM; McCormick, BJJ; Platts-Mills, J; Seidman, JC; Blank, RR; Gottlieb, M; Knobler, SL; Lang, DR; Miller, MA; Tountas, KH; Checkley, W; Mason, CJ; Murray-Kolb, LE; Petri, WA; Bessong, P; Haque, R; John, S; Mduma, ER; Oriá, RB; Shrestha, PS; Shrestha, SK; Svensen, E; Zaidi, AKM; Abreu, CB; Acosta, AM; Ahmed, I; Shamsir Ahmed, AM; Ali, A; Ambikapathi, R; Barrett, L; Bauck, A; Bayyo, E; Bodhidatta, L; Bose, A; Daniel Carreon, J; Chandyo, RK; Charu, V; Costa, H; Dillingham, R; Di Moura, A; Doan, V; Filho, JQ; Graham, J; Hoest, C; Hossain, I; Islam, M; Steffi Jennifer, M; Kaki, S; Koshy, B; Leite, ÁM; Lima, NL; Maciel, BLL; Mahfuz, M; Mahopo, C; Maphula, A; McGrath, M; Mohale, A; Moraes, M; Mota, FS; Muliyil, J; Mvungi, R; Nayyar, G; Nyathi, E; Olortegui, MP; Oria, R; Vasquez, AO; Pan, WK; Pascal, J; Patil, CL; Pendergast, L; Pinedo, SR; Psaki, S; Raghava, MV; Ramanujam, K; Rasheed, M; Rasmussen, ZA; Richard, SA; Rose, A; Roshan, R; Schaefer, B; Scharf, R; Sharma, SL; Shrestha, B; Shrestha, R; Simons, S; Soares, AM; Mota, RMS; Soofi, S; Strand, T; Tofail, F; Thomas, RJ; Turab, A (2017-04-01)
      © 2017 The Authors 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.
    • Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: Findings from the MAL-ED birth cohort study

      Murray-Kolb, LE; Acosta, AM; De Burga, RR; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Salas, MS; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Bhutta, ZA; Qureshi, S; Rasheed, M; Soofi, S; Turab, A; Zaidi, AKM; Bodhidatta, L; Mason, CJ; Babji, S; Bose, A; George, AT; Hariraju, D; Jennifer, MS; John, S; Kaki, S; Kang, G; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Bose, A; Roshan, R; Sharma, SL; Sundaram, SE; Thomas, RJ; Pan, WK; Ambikapathi, R; Carreon, JD; Charu, V; Doan, V; Graham, J; Hoest, C; Knobler, S; Lang, DR; McCormick, BJJ; McGrath, M; Miller, MA; Mohale, A; Nayyar, G; Psaki, S; Rasmussen, Z; Richard, SA; Seidman, JC; Wang, V; Blank, R; Gottlieb, M; Tountas, KH; Amour, C; Bayyo, E; Mduma, ER; Mvungi, R; Nshama, R; Pascal, J; Swema, BM; Yarrot, L; Ahmed, T; Ahmed, AMS; Haque, R; Hossain, I; Islam, M; Mahfuz, M; Mondal, D; Tofail, F; Chandyo, RK; Shrestha, PS; Shrestha, R; Ulak, M; Bauck, A; Black, RE; Caulfield, LE; Checkley, W; Kosek, MN; Lee, G; Schulze, K; Yori, PP; Murray-Kolb, LE; Catharine Ross, A; Schaefer, B; Simons, S; Pendergast, L; Abreu, CB; Costa, H (2018-07-01)
      © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. background Millions of children in low-income and middle-income countries (LMICs) are at risk of not reaching their full cognitive potential. Malnutrition and enteric infections in early life are implicated as risk factors; however, most studies on these risks and their associations with cognitive development have failed to adequately account for confounding factors or the accumulation of putative insults. Here, we examine the interaction between infections and illness on cognitive development in LMIC community settings. Methods As part of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study, children from eight LMICs were followed from birth to 24 months to understand the influence of repeated enteric infections on child growth and development. Here, data from six sites were employed to evaluate associations between infection, illness, the home environment, micronutrient intake and status, maternal reasoning, and cognitive development at 24 months. results Higher rates of enteropathogen detection and days with illness were associated with lower haemoglobin concentrations, which in turn were associated with lower cognitive scores at 24 months. Children with lower environmental health/safety scores and lower intakes of vitamin B 6 and folate had more enteropathogen detections and illness. Strength of associations varied by weight-for-age in the first 17 days of life; lower weight infants were more susceptible to the negative effects of enteropathogens and illness. Conclusions Enteropathogens were negatively related to child cognitive development. However, other factors were more strongly associated with child cognition. Targeting of interventions to improve cognitive development should include a focus on reducing frequency of illness, improving the safety and healthfulness of the child's environment, and improving dietary intake.
    • Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: Findings from the MAL-ED birth cohort study

      Acosta, AM; De Burga, RR; Chavez, CB; Flores, JT; Olotegui, MP; Pinedo, SR; Salas, MS; Trigoso, DR; Vasquez, AO; Ahmed, I; Alam, D; Ali, A; Bhutta, ZA; Qureshi, S; Rasheed, M; Soofi, S; Turab, A; Zaidi, AKM; Bodhidatta, L; Mason, CJ; Babji, S; Bose, A; George, AT; Hariraju, D; Steffi Jennifer, M; John, S; Kaki, S; Kang, G; Karunakaran, P; Koshy, B; Lazarus, RP; Muliyil, J; Raghava, MV; Raju, S; Ramachandran, A; Ramadas, R; Ramanujam, K; Bose, A; Roshan, R; Sharma, SL; Shanmuga Sundaram, E; Thomas, RJ; Pan, WK; Ambikapathi, R; Daniel Carreon, J; Charu, V; Doan, V; Graham, J; Hoest, C; Knobler, S; Lang, DR; McCormick, BJJ; McGrath, M; Miller, MA; Mohale, A; Nayyar, G; Psaki, S; Rasmussen, Z; Richard, SA; Seidman, JC; Wang, V; Blank, R; Gottlieb, M; Tountas, KH; Amour, C; Bayyo, E; Mduma, ER; Mvungi, R; Nshama, R; Pascal, J; Swema, BM; Yarrot, L; Ahmed, T; Shamsir Ahmed, AM; Haque, R; Hossain, I; Islam, M; Mahfuz, M; Mondal, D; Tofail, F; Chandyo, RK; Shrestha, PS; Shrestha, R; Ulak, M; Bauck, A; Black, RE; Caulfield, LE; Checkley, W; Kosek, MN; Lee, G; Schulze, K; Yori, PP; Murray-Kolb, LE; Catharine Ross, A; Schaefer, B; Simons, S; Pendergast, L; Abreu, CB; Costa, H; Di Moura, A (2017-01-01)
      © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. Background Dietary and illness factors affect risk of growth faltering; the role of enteropathogens is less clear. As part of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, we quantify the effects of enteropathogen infection, diarrhoea and diet on child growth. Methods Newborns were enrolled and followed until 24 months. Length and weight were assessed monthly. Illnesses and breastfeeding practices were documented biweekly; from 9 to 24 months, non-breast milk intakes were quantified monthly. Routinely collected non-diarrhoeal stools were analysed for a broad array of enteropathogens. A linear piecewise spline model was used to quantify associations of each factor with growth velocity in seven of eight MAL-ED sites; cumulative effects on attained size at 24 months were estimated for mean, low (10th percentile) and high (90th percentile) exposure levels. Additionally, the six most prevalent enteropathogens were evaluated for their effects on growth. results Diarrhoea did not have a statistically significant effect on growth. Children with high enteropathogen exposure were estimated to be 1.21±0.33 cm (p<0.001; 0.39 length for age (LAZ)) shorter and 0.08±0.15 kg (p=0.60; 0.08 weight-for-age (WAZ)) lighter at 24 months, on average, than children with low exposure. Campylobacter and enteroaggregativeEscherichia coli detections were associated with deficits of 0.83±0.33 and 0.85±0.31 cm in length (p=0.011 and 0.001) and 0.22±0.15 and 0.09±0.14 kg in weight (p=0.14 and 0.52), respectively. Children with low energy intakes and protein density were estimated to be 1.39±0.33 cm (p<0.001; 0.42 LAZ) shorter and 0.81±0.15 kg (p<0.001; 0.65 WAZ) lighter at 24 months than those with high intakes. conclusions Reducing enteropathogen burden and improving energy and protein density of complementary foods could reduce stunting.