Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome?

Abstract

Hypotheses regarding the developmental origins of health and disease postulate that developing fetuses - and potentially young children - undergo adaptive epigenetic changes that have longstanding effects on metabolism and other processes. Ongoing research explores whether these adaptations occur during early life following early childhood malnutrition. In the developing world, there remains a high degree of nutritional stunting, defined as linear growth failure caused by inadequate caloric intake, which may be exacerbated by inflammation from ongoing infections. In areas with poor sanitation, children experience vicious cycles of enteric infections and malnutrition, resulting in poor nutrient absorption as a result of changes in the intestinal mucosa, now termed "environmental enteropathy." Emerging evidence links early childhood diarrhea and/or growth failure with an increased occurrence of risk factors for cardiovascular disease in later life, including dyslipidemia, hypertension, and glucose intolerance. The mechanisms for these associations remain poorly understood and may relate to epigenetic responses to poor nutrition, increased inflammation, or both. Given the increased incidence of cardiovascular disease in developing areas of the world, associations between childhood malnutrition, early-life infections, and the increased occurrence of risk factors for cardiovascular disease underscore further reasons to improve nutrition and infection-related outcomes for young children worldwide.

Figure 1. Environmental enteropathy: villus atrophy and a cycle of infections and malnutrition

Children in developing areas in the world frequently exhibit abnormalities in their intestinal mucosa referred to as “environmental enteropathy.” Associated findings following on biopsy of the intestinal mucosa include villus blunting and deepened crypts (A) compared to normal mucosa (B). C. As shown in this model, these cases of environmental enteropathy are thought to be due to reciprocal relationships between malnutrition and recurrent enteric infections due in part to contaminated drinking water and poor sanitation. This cycle of undernutrition ultimately leads to poor weight gain and stunting. (From McKay International Health 2010; 2: 172–180, Levine BMC Biology 2010; 8:129 and Guerrant Nutr Rev 2008; 66:487–505, used by permission.)

Figure 2. Meta-analysis of the relationship between diarrheal illnesses and stunting in the developing world

A. Point estimates and confidence intervals for the odds of stunting at 2 y.o. in children who had at least 5 episodes of diarrhea compared with those with less than 5 episodes. B. There was a linear relationship between the cumulative diarrheal incidence before 2 y.o. vs. the log odds of stunting at 2 y.o., suggesting a dosage effect of diarrhea on stunting. (From Checkley International J of Epidemiology 2008; 37:816–830, used by permission.)

Figure 3. Individuals who develop CVD and glucose intolerance on average exhibit poor early childhood growth

A. Childhood growth characteristics of 357 men who developed coronary heart disease as adults. Mean values for age of height, weight and BMI z-score for the overall sample (4630 boys) is set to a z-score of zero. On average, men who developed coronary heart disease exhibited below average growth parameters in early life followed by rapid weight gain in later childhood. B. Childhood BMI z-score of 156 individuals found to have glucose intolerance at age 25–34 years. The mean childhood BMI for the overall sample (1492 individuals evaluated as adults) is set to a z-score of zero. Individuals with glucose intolerance as adults exhibited a mean childhood BMI z-score (solid line, with confidence intervals as dotted lines) that was below average in early life followed by rapid weight gain later. (From Barker NEJM 2005; 353: 1802–1809 and Bhargava NEJM 2004; 350: 865–875; used by permission.)

Figure 4. Model for the effects of early childhood nutrition on adult health

According to hypothesies related to the early origins of adult disease, intrauterine growth restriction leads to epigenetic changes, affecting adult health outcomes. Data are beginning to accumulate that these changes may not be complete at birth but may be affected by further malnutrition and inflammation in early childhood. The mechanistic basis for this (and the ultimate effect on adult health outcomes) is not yet known.