Characterising metabolic signatures of health status in Australian children and adults: A targeted metabolomic approach

Abstract

Human disease risk is the result of a complex interaction between endogenous factors (e.g. genetic, transcriptomic, epigenetic, and metabolic) and exogenous exposures (e.g. diet, physical activity, smoking, and lifestyle). Metabolomics is the study of the substrates, intermediates, and products of metabolic reactions present within a biological entity (i.e. organisms, tissues, cells, or biofluids). Advances in metabolomics profiling have rendered the high-throughput detection, quantitation, and identification of such metabolites in biological matrices relatively straightforward. Nutritional metabolites measured in human biological fluids (e.g. amino acids, one-carbon (1-C) metabolites, Trimethylamine N-oxide (TMAO), carnitine) are at the intersection of endogenous and exogenous exposures and have proven useful in the prediction of future health and disease outcomes. In this thesis, I have developed and robotically-automated a targeted metabolomics method; characterised plasma homeostatic concentrations of essential and non-essential amino acids, Trimethylamine NOxide (TMAO) and its precursors carnitine, choline, betaine, and dimethylglycine (DMG); and identified associations between the concentrations of TMAO and those of its precursors with self-reported animal protein and fast food intakes, as well as cardiometabolic outcomes in a cohort of Australian children (N=1,166) and their parents (N=1,324). Strong family (parentchild) associations, as well as age, and sex differences were identified in the levels of these nutritional metabolites. Self-reported intakes of fish and meat were positively associated with plasma TMAO concentrations in both children and adults. Choline, betaine, dimethylglycine (DMG), and carnitine, but not TMAO, were strongly associated with metabolic syndrome scores, and cardiovascular phenotypes by potentially being involved in key physiological pathways that do not involve TMAO. In conclusion, family, sex, and age characterise the levels of nutritional metabolites that are associated with adverse metabolic outcomes. Ultimately, a personalised interpretation of nutritional profiles in relation to health outcomes should be performed within the metabolic, dietary, and epidemiological context of an individual.