Antibiotics in early life and obesity

Abstract

The intestinal microbiota can influence host metabolism. When given early in life, agents that disrupt microbiota composition, and consequently the metabolic activity of the microbiota, can affect the body mass of the host by either promoting weight gain or stunting growth. These effects are consistent with the role of the microbiota during development. In this Perspective, we posit that microbiota disruptions in early life can have long-lasting effects on body weight in adulthood. Furthermore, we examine the dichotomy between antibiotic-induced repression and promotion of growth and review the experimental and epidemiological evidence that supports these phenotypes. Considering the characteristics of the gut microbiota in early life as a distinct dimension of human growth and development, as well as comprehending the susceptibility of the microbiota to perturbation, will allow for increased understanding of human physiology and could lead to development of interventions to stem current epidemic diseases such as obesity, type 1 diabetes mellitus and type 2 diabetes mellitus.

Figure 1. A model of microbiota transmission, maturation and perturbation in the first years of life and possible effects on weight

New born infants receive much of their initial colonizing microbiota at birth. Founding bacterial communities are transferred from the mother's vagina and perineum at birth, through skin contact and consumption of breast milk during nursing, and via skin and oral contact with general care and maternal interaction. The microbial communities may be affected before initial colonization by maternal antibiotic use or by circumventing normal colonization routes (for example, Caesarean-section delivery). The infant microbiota undergoes maturation and increases in diversity and stability, resembling the microbiota of adult individuals by the age of three years. As a result of its instability, the microbiota in infancy is particularly vulnerable to antibiotic disruption, and having an altered microbiota can effect growth and development later in life. Based on the evidence that the microbiota can participate in metabolic signalling and nutrient extraction, perturbations in their early-life populations may result in divergent metabolic outcomes, including excessive weight gain or stunted development. In theory, it is likely that these disruptions must pass a threshold to exert an effect, and a limited perturbation with rapid recovery might not result in altered weight or adiposity. The microbiota-induced metabolic changes are layered on top of other factors that also can have a strong effect on metabolic development, including genetic predisposition, gender, diet, physical activity, disease, or environmental toxicants.

Figure 2. Proposed pathways of antibiotic-mediated weight modulation

Exposures to high-dose antibiotics that cause extensive and sustained reductions in microbiota populations early in life can stunt growth and lead to underdevelopment. The intermediate steps could involve altered immunological signalling or decreased production of microbiota-derived calories and nutrients—a weight loss effect that is enhanced when the diet is deficient in essential amino acids that can be contributed by the microbiota. Antibiotic treatments in early life that alter microbiota composition, but that have limited effects on the overall microbial population size, can lead to weight gain—potentially by reducing key metabolically protective microbiota species, increasing productions of microbiota-derived calories (such as short-chain fatty acids), altering hepatic function and levels of circulating metabolic hormones or by altering intestinal defences (lowering energy costs). In these divergent scenarios, the disturbance to the microbiota would likely need to exceed a threshold beyond a mild-perturbation of short duration to yield a clinical phenotype.