Identification of nutritionally modifiable hormonal and epigenetic drivers of positive and negative growth deviance in rural African fetuses and infants: Project protocol and cohort description

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Abstract

Growth retardation (stunting, wasting and poor organ development) among children in low-income countries has major short and long-term health consequences yet very little is known about the nutritional and environmental influences on the key hormonal axes regulating child growth in these settings, nor the tempo and timing of faltering episodes. Here we describe the study protocol and provide a cohort description of the Hormonal and Epigenetic Regulators of Growth (HERO-G) study. This prospective cohort study from rural Gambia, West Africa, followed mothers and children longitudinally from pre-conception, through pregnancy, delivery, and to two years of child age

A total of 251 eligible mother-infant pairs were recruited into the HERO-G study, with 206 (82%) followed up until two years of age. Women were seen at scheduled antenatal appointments at 20, 28 and 36 weeks of gestation, and at delivery, where possible. Between one week and 12 months of age, infants were visited every second day for collection of detailed anthropometry and morbidity data. Infants identified as about to enter a growth faltering episode at these visits entered a more detailed 20-day protocol, with the collection of dried blood spots, anthropometry and body composition. All infants were seen for scheduled clinic visits at 3, 6, 9, 12, 18 and 24 months of age for clinical examination and venous blood draw.

Data from the HERO-G study is being used to explore three major mechanistic pathways influencing growth: 1) genome-wide investigations for signatures of epigenetic effects on any loci that might affect growth; 2) frequent anthropometric measurement coupled with non-invasive monitoring for rapid identification and interrogation of real-time faltering patterns and aetiology; 3) focused measurement of hormones and cytokines that act together in an integrated manner, both in utero and after birth, to coordinate patterns of growth with immune activation, inflammation, and nutritional status.

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Most cited references 24

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Maternal and child undernutrition and overweight in low-income and middle-income countries

Robert E Black, Cesar G Victora, Susan P. Walker … (2013)

The Lancet, 382(9890), 427-451

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Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation.

Michael P Lunn, Lahcen I. Campbell, Evelin Elia (2003)

Growth faltering of rural Gambian infants is associated with a chronic inflammatory enteropathy of the mucosa of the small intestine that may impair both digestive/absorptive and barrier functions. The aim of this study was to determine whether the enteropathy was associated with a compromised barrier function that allowed translocation of antigenic macromolecules from the gut lumen into the body, with subsequent systemic immunostimulation, resulting in growth retardation. Rural Gambian infants were studied longitudinally at regular intervals between 8 and 64 wk of age. On each study day, each child was medically examined, anthropometric measurements were made, a blood sample was taken and an intestinal permeability test performed. Evidence of chronic immunostimulation was provided by abnormally elevated white blood cell, lymphocyte and platelet counts, and frequently raised plasma concentration of C-reactive protein. Intestinal permeability was abnormal and associated with impaired growth (r = -0.41, P < 0.001). Plasma concentrations of endotoxin and immunoglobulin (Ig)G-endotoxin core antibody were also elevated and related to both growth (r = -0.30, P < 0.02; r = -0.64, P < 0.0001, respectively) and measures of mucosal enteropathy. Plasma IgG, IgA and IgM levels increased rapidly with age toward adult concentrations. Raised values were related to poor growth but also to measures of mucosal enteropathy and the endotoxin antibody titer. The interrelationships among these variables and growth suggested that they were all part of the same growth-retarding mechanism. These data are consistent with the hypothesis of translocation of immunogenic lumenal macromolecules across a compromised gut mucosa, leading to stimulation of systemic immune/inflammatory processes and subsequent growth impairment.

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Intestinal permeability, mucosal injury, and growth faltering in Gambian infants.

R Downes, Nicole Northrop, Michael P Lunn (1991)

There is controversy over whether children in developing countries can catch up on their growth rates after bouts of diarrhoea. A factor influencing catch-up growth is the extent and duration of mucosal injury. To explore the relation between intestinal disease and growth performance, a non-invasive test of intestinal integrity, the lactulose:mannitol permeability test, was done regularly on children aged 2-15 months, whose growth was monitored over a mean of 7.5 months. The study revealed persistent abnormalities in the small bowel mucosa of 2-15 month old Gambian infants and a negative correlation between these abnormalities and growth. Up to 43% of observed growth faltering can be explained on the basis of these long-term intestinal lesions.