Physiological function in children with stunting in rural Zimbabwe

Undernutrition affects a quarter of children globally. Stunting, when children do not grow as tall as they should for their age, leads to ill-health into adult life due to diseases like high blood pressure, heart attacks and diabetes. Since these conditions often occur together in the same person, we call this "multimorbidity". We do not fully understand why poor growth increases the risk of these diseases, but we want to test the theory that short stature is accompanied by poor growth and function of vital organs. We want to explore whether signs of organ damage are already apparent in childhood, and whether an intensive nutrition intervention - which helped children to grow taller in the first 2 years of life - also helps their muscles, bones, and organs grow more healthily by the time they reach 9 years of age. We believe that inflammation (the body's normal response to wounding or infection) is excessive in children with stunting, further damaging the development and function of key organs, and leading to a lifelong risk of ill-health. If this is true, nutrition interventions alone may not be enough, and we need to find new ways to tackle the body's inflammatory response to stop further organ damage.

We will follow up a group of children in rural Zimbabwe who were enrolled into a previous clinical trial, which randomised (like the flip of a coin) some children to receive nutritional supplements in the first 18 months of life, and some children to receive their regular household diet. The children who received the nutritional supplements grew taller and were less likely to be stunted at 18 months of age. These children are now turning 9 years old, and this provides a chance for us to investigate the long-term effects of stunting, and to explore whether the nutrition intervention has sustained health benefits. We will do detailed testing of children's muscle quality, bone strength, lung size, heart function, kidney length, the amount of fat in the body, and how well a child can control their blood sugar levels, to see whether poor growth affects how children's bodies function by mid-childhood. These might be 'early warning signs' of a lifelong risk of disease, because we know that the size of a child's lungs, for example, tracks into adult life, and that poor lung function is linked to a risk of early death. We can compare test results between children who did or did not get the nutritional supplements in early life, to see whether the children who grew taller due to the supplements now have stronger bones and muscles, bigger lungs and kidneys, better heart function, and less body fat. Finally, by using blood samples collected at 9 years of age, we can test our theory that high levels of inflammation persist during childhood and are associated with reduced organ function.

If children with stunting have signs of poor organ function at school age, then it suggests the lifelong impact of stunting on adult diseases like heart attacks is already emerging in childhood. We think prevention should start very early in life. If we find that the nutritional supplements have had long-term benefits for children's bones, muscles and organs, this provides a very powerful message to policymakers: we should be scaling up our efforts to supplement children's diets soon after birth, because the benefits may stretch into mid-childhood and beyond. If we find that the body's inflammatory processes are driving ongoing organ damage, there may still be an opportunity to intervene at school age, to stop progression of this damage, rather than waiting for conditions like high blood pressure and diabetes to become apparent in adult life. This study would provide the information we need to design new approaches that can tackle inflammation - such as dietary changes, exercise programmes, or anti-inflammatory drugs - to halt the damage, and ensure that all children can become healthy and productive adults.

Child stunting is associated with increased lifelong non-communicable disease (NCD) risk. We believe stunting elevates NCD risk by restricting organ growth, and that chronic inflammation during childhood drives organ dysfunction. We hypothesise subclinical changes in organ function are already apparent by mid-childhood in multiple systems, increasing long-term multimorbidity risk. We believe organ function is partially improved with early-life nutrition interventions, and that chronic inflammation needs to be tackled in tandem with promoting healthy growth, due to its deleterious effects on organ function.

We will leverage follow-up of a birth cohort in rural Zimbabwe, who received a randomised nutrition intervention to 18 months of age, and are now 9 years old. We will phenotype organ function, metabolic capacity, muscle quality and bone architecture to identify early signs of organ dysfunction, before clinical disease is apparent. We will evaluate associations between early-life stature and school-age physiological function, using generalised estimating equations (GEE), adjusting for confounders. Next, we will assess the impact of early-life nutrition on physiological function at 9 years, capitalising on the randomised trial design, in an intention-to-treat analysis. Finally, we will measure multiplex plasma biomarkers at 9 years to define the persistent inflammatory pathways associated with organ dysfunction, using principal components analysis to identify biomarker combinations, and GEE models to explore associations with physiological function.

Our results will define the timing of onset of organ and metabolic dysfunction, the underlying pathways, and the potential for prevention. If early-life nutrition has long-term benefits, it provides a strong rationale for global scale-up; if we find evidence of damaging chronic inflammation, then new anti-inflammatory approaches may be required. Early intervention would provide a step-change in NCD prevention.