The association between body mass index and metabolite response to a liquid mixed meal challenge

Background Metabolite abundance is a dynamic trait that is not only variable in a fasting state, but also varies in response to environmental stimuli, such as food consumption. Postprandial abundance and response to a meal are emergent traits in studies of disease and which themselves may be subject to specific risk factors. We investigated body mass index (BMI) as a recognized risk factor for numerous health outcomes that may influence metabolite response to feeding. Here we use the Netherlands Epidemiology of Obesity (NEO) study to examine associations between BMI and metabolite response to a liquid meal and extend this by using Mendelian randomization (MR) to estimate potential causal effects. Methods and findings The NEO study conducted a liquid meal challenge and collected metabolite profiles using the Nightingale metabolomics platform in 5744 study participants. Observational and one-sample MR analysis were conducted to estimate the effect of BMI on metabolites and ratios of metabolites (n = 229) in the fasting, postprandial and response (or change in abundance) states. After an appropriate multiple testing correction, we observed 473 associations with BMI (175 fasting, 188 postprandial, 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, 3 response) to be associated with BMI. In both the fasting and postprandial state, this included citrate and the ratios of linoleic acid, omega-6 fatty acid and polyunsaturated fatty acids to total fatty acids. In addition, the glucogenic amino acid alanine was inversely associated with BMI in the response state, suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI. Conclusions Overall, MR estimates were strongly correlated with observational effect estimates suggesting that the broad associations seen between BMI and metabolite variation in fasting, postprandial and response states have a causal underpinning. Specific effects in previously unassessed postprandial and response states were detected and these may likely mark novel life course risk exposures driven by regular nutrition.