Nutrition Publication

Early Programming Effects of Nutrition – Life-Long Consequences?

Editor(s): F. M. Ruemmele. 69 / 2

This issue of the Annales shows that the development of extremely frequent diseases, such as cardiovascular or metabolic disorders, are at least in part programmed by events early in life.  Convincing data indicating that there is a window of opportunity for programming or malprogramming via nutritional interventions are presented.

Related Articles

Epigenetic Epidemiology: The Rebirth of Soft Inheritance

Author(s): M. Hanson, F. Low, P. Gluckman

Non-communicable diseases (NCDs), such as cardiovascular disease and type 2 diabetes, constitute the main cause of death worldwide. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socio-economic improvement following reductions in the burden of infectious disease. The World Health Organization predicts a substantial increase in the incidence of NCDs over the next decade globally. NCDs are generally preventable, but current approaches are clearly inadequate. New initiatives are needed to implement such prevention, and there needs to be greater recognition that early-life interventions are likely to be the most efficacious.Devising appropriate prevention strategies necessitates an understanding of how the developmental environment influences risk. Progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility.However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and ‘soft’ inheritance in modulating an individual’s vulnerability to NCD. This also offers opportunities for novel epigenetic biomarkers of risk or interventions  targeting epigenetic pathways to be devised for use in early life. This may pave the way to much more effective, customised interventions to promote health across the life course.

Programming towards Childhood Obesity

Author(s): P. Tounian

There is now considerable evidence that a constitutional susceptibility to fat gain is necessary for children to become obese under the pressure of an obesogenic environment; this is the programming towards obesity. The role of genetics in this programming is dominant. Besides the rare monogenic recessive forms of obesity secondary to mutations in genes involved in the hypothalamic appetite control path-ways, obesity linked to mutations in melanocortin 3 and 4 receptors are more frequent due to their dominant mode of transmission. Predisposition to common obesity is polygenic and involves a network of genes; nevertheless, more research is required to elucidate their exact role. Fetal and perhaps early postnatal programming is also possible. Underand overnutrition, diabetes, and maternal smoking during pregnancy were shown to promote later obesity and may affect the central body weight regulatory system during fetal development. The role of early postnatal factors such as formula-feeding rather than breastfeeding, excess in n–6 polyunsaturated fatty acids or protein intakes, and excessive weight gain early in life is more questionable and needs further investigation. Taking into consideration that childhood obesity is a programmed disease should modify its clinical management. Childhood obesity should no longer be considered as the result of inappropriate eating habits and/or excessive inactivity in order to relieve the obese children’s discrimination and their parents’ guilt. Since treatment of obese children requires a substantial motivation to continuously fight against the programmed excessive drive to eat, it seems wiser to wait for children to be old enough, thus more motivated, to initiate energy restriction. Moreover, with the great majority of children being not predisposed to obesity, prevention strategies should not be addressed to the whole pediatric population but targeted to those children at risk. Improvement of knowledge on programming towards obesity is essential to develop more promising therapeutic andpreventive approaches.

Metabolic Programming in the Immediate Postnatal Life

Author(s): M. Patel, M. Srinivasan

The metabolic programming effects of nutritional modifications in the immediate postnatal life are increasingly recognized to independently contribute to the development of metabolic syndrome in later life. Adjustment of litter size in rodents has been used to induce either under- or overnourishmentin the immediate postnatal life of the offspring. While undernourishment led to growth retardation in the offspring, overnourishment produced increased body weight gains, hyperinsulinemia and hyperleptinemia. Over-nourishment during the suckling period induced several adaptations in the energy circuitry in the hypothalamus of the offspring predisposing them for the onset of obesity later in life. Another approach for a nutritional modification in the immediate postnatal period is the artificial rearing of newborn rat pups on a high-carbohydrate (HC) milk formula without changes in the total calorie availability. Hyperinsulinemia, immediately evident in the HC pups, persisted in the post-weaning period even after withdrawal of the HC milk. Significant alterations in pancreatic islets supported chronic hyperinsulinemia in the HC rats. Alterations in the gene expression of hypothalamic neuropeptides predisposing to hyperphagia were evident during the period of the HC dietary modification. The persistence of these hypothalamic adaptations supported the obese phenotype in adult HC rats. A transgenerational effect gave rise to the development of chronic hyperinsulinemia and adult-onset obesity in the offspring of the HC female rats. Other studies have shown that lactation by a diabetic, obese or malnourished mother resulted in predisposition for the onset of metabolic disorders in the offspring. These observations from animal studies on the metabolic programming effects due to altered nutritional experiences in the immediate postnatal life strongly suggest that altered feeding practices for infants (formula feeding and early introduction of infant foods) could contribute to the rising incidence of overweight/obesity in children and adults.

Programming of Host Metabolism by the Gut Microbiota

Author(s): F. Bäckhed

The human gut harbors a vast ensemble of bacteria that has co-evolved with the human host and performs several important functions that affect our physiology and metabolism. The human gut is sterile at birth and is subsequently colonized with bacteria from the mother and the environment. The complexity of the gut microbiota is increased during childhood, and adult humans contain 150-fold more bacterial genes than human genes. Recent advances in nextgeneration sequencing technology and mechanistic testing in gnotobiotic mice have identified the gut microbiota as an environmental factor that contributes to obesity. Germ-free mice are protected against developing diet-induced obesity and the underlying mechanisms whereby the gut microbiota contributes to host metabolism are beginning to be clarified. The obese phenotype is associated with increased mi-crobial fermentation and energy extraction; however, other microbially modulated mechanisms contribute to disease progression as well. The gut microbiota has profound effects on host gene expression in the enterohepatic system, including genes involved in immunity and metabolism. For example, the gut microbiota affects expression of secreted proteins in the gut, which modulate lipid metabolism in peripheral organs. In addition, the gut microbiota is also a source of proinflammatory molecules that augment adipose inflammation and macrophage recruitment by signaling through the innate immune system. TLRs (Toll-like receptors) are integral parts of the innate immune system and are expressed by both macrophages and epithelial cells. Activation of TLRs in macrophages dramatically impairs glucose homeostasis, whereas TLRs in the gut may alter the gut microbial composition that may have profound effects on host metabolism. Accordingly, reprogramming the gut microbiota, or its function, in early life may have beneficial effects on host metabolism later in life.