The life-long effects of maternal milk: programming offspring development

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In Canada, 22-24% of women are diagnosed with obesity at the time of conception. Maternal obesity is not only associated with negative outcomes for the mother, but it can impact fetal and postnatal development and the overall health of offspring in later life. Maternal milk consumption is proposed as a solution to combat the risks of obesity in offspring. However, very little is known about the underlying biological mechanisms that infer this protective effect and how maternal nutrition may influence the composition and function of the non-nutritive, bioactive components of milk. Mammalian milk is a complex biological fluid that contains a plethora of bioactive components. My focus is on a group of small, fat-coated, bioactive vesicles known as milk-derived exosomes (MDEs). MDEs are a unique subpopulation of extracellular vesicles that survive digestion, travel long-distances (gut to the brain), and carry genetic information from mothers to their offspring. One of the main types of genetic information packaged within MDEs, is milk microRNAs (miRNAs), small RNA that blocks protein production in recipient cells. This establishes a novel, post-birth molecular route of mother-offspring communication, that is heavily understudied. My long-term objective is to characterize the role of MDEs and milk miRNAs as biological regulators in early postnatal development. Over the next five years, I will address four short-term objectives: 1) using cell culture and a rodent model map the cellular and molecular mechanisms of MDEs and milk miRNA transfer across the gut and into the brain, 2) quantify changes in MDE and milk miRNA composition across milk types and lactation age, 3) explore how maternal nutrition stress affect lactation biology of the mother, and 4) how does changes in lactation biology influence developmental trajectories in offspring. Completing studies under objective 1 will enable me to understand the cellular mechanisms that control MDE and milk miRNA transport in tissues (especially in the brain, where very little information is known to date). Objective 2 will build on objective 1 to characterize temporal changes in the composition of MDEs and miRNAs in milk type (colostrum and mature milk). Addressing objective 3 and 4 will allow me to expand my research into the developmental origins of health and disease field, where milk-induced phenotypic and physiological outcomes in offspring due to maternal nutrition stress will be investigated. My aim is to improve our understanding of the molecular basis of lactation biology and identify novel methods of postnatal communication between mother and child. I anticipate that my research will identify genes and developmental pathways that are regulated by MDEs and milk miRNAs. Mechanistic insights obtained from this research can be used to improve nutritional benefits of donor and formula feeding, where MDE and milk miRNA-based signalling is absent.