Urinary metabolomics reveals glycemic and coffee associated signatures of thyroid function in two population-based cohorts

Abstract

BackgroundTriiodothyronine (T3) and thyroxine (T4) as the main secretion products of the thyroid affect nearly every human tissue and are involved in a broad range of processes ranging from energy expenditure and lipid metabolism to glucose homeostasis. Metabolomics studies outside the focus of clinical manifest thyroid diseases are rare. The aim of the present investigation was to analyze the cross-sectional and longitudinal associations of urinary metabolites with serum free T4 (FT4) and thyroid-stimulating hormone (TSH).MethodsUrine Metabolites of participants of the population-based studies Inter99 (n = 5620) and Health2006/Health2008 (n = 3788) were analyzed by 1H-NMR spectroscopy. Linear or mixed linear models were used to detect associations between urine metabolites and thyroid function.ResultsCross-sectional analyses revealed positive relations of alanine, trigonelline and lactic acid with FT4 and negative relations of dimethylamine, glucose, glycine and lactic acid with log(TSH). In longitudinal analyses, lower levels of alanine, dimethylamine, glycine, lactic acid and N,N-dimethylglycine were linked to a higher decline in FT4 levels over time, whereas higher trigonelline levels were related to a higher FT4 decline. Moreover, the risk of hypothyroidism was higher in subjects with high baseline trigonelline or low lactic acid, alanine or glycine values.ConclusionThe detected associations mainly emphasize the important role of thyroid hormones in glucose homeostasis. In addition, the predictive character of these metabolites might argue for a potential feedback of the metabolic state on thyroid function. Besides known metabolic consequences of TH, the link to the urine excretion of trigonelline, a marker of coffee consumption, represents a novel finding of this study and given the ubiquitous consumption of coffee requires further research.

Empowering thyroid hormone research in human subjects using OMICs technologies

“…Consequently, the evaluation of kidney function from circulating parameters in the context of thyroid disorders is severely hampered. A relationship between thyroid state and the plasma levels of asymmetric dimethylarginine align well with the observations of diminished urinary excretion of dimethylamine noted earlier (Friedrich et al 2017) and the concordant decline in plasma citrulline levels within the study further fits in this context. Hence, the metabolism of asymmetric dimethylarginine is a simple example to reveal novel putatively TH-dependent pathways.…”

“…We screened similar urine metabolomics data for a molecular signature preceding shifts in TSH and FT 4 among two large population-based studies from Denmark (Friedrich et al 2017). Apart from otherwise confirmative results, urine levels of alanine were strongly positively associated with a shift in FT 4 concentrations during the observation period.…”

“…Importantly, only minor overlap with the classical markers of thyroid function became obvious, comprising trigonelline (FT 4 ) and hippurate (TSH). We presumed altered peripheral conversion of TH following coffee consumption (Friedrich et al 2017) (with trigonelline and in part hippurate as surrogate markers) and high FT 4 levels might therefore align with high 3,5-T 2 levels. However, the direct relationship between 3,5-T 2 , FT 4 and trigonelline represents a matter of future research.…”

“…alanine utilization in the liver), which is subsequently counteracted at least in part by adaptations in FT 4 levels. We further leveraged the metabolomics coverage of exogenous influences to highlight a dependency between urine trigonelline and FT 4 , a known surrogate marker of coffee consumption (Friedrich et al 2017). Another metabolite of interest was dimethylamine (also associated to TSH), which is either produced by gut microbiota or as degradation product of asymmetric dimethylarginine, a potent vasodilator (Fig.…”

A new workflow combining R packages for statistical analysis of metabolites

“…Accordingly, the analogous research question in food metabolomics concerns the relationship between food metabolome and food cultivar. See for instance [2,7,21,20,16,6] and the articles cited there. However, the demonstration of such relationships is a challenging task, since the metabolomics data are complex and many issues are to be simultaneously managed, as we shall discuss later.…”