The association between body mass index and metabolite response to a liquid mixed meal challenge: a Mendelian randomization study

Metabolite abundance is a dynamic trait that varies in response to environmental stimuli and phenotypic traits, such as food consumption and body mass index (BMI). Here we use the Netherlands Epidemiology of Obesity (NEO) study to identify observational and causal associations between BMI and metabolite response to a liquid meal. A liquid meal challenge was performed and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample MR analysis were conducted to estimate the effect of BMI on metabolites (n = 229) in the fasting, postprandial and response (or change in abundance) states. 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. MR associations included the glucogenic amino acid alanine which was inversely associated with BMI in the response state (beta = -0.081, se = 0.023, P = 5.91x10-4), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI. Overall, MR estimates were strongly correlated with observational effect estimates suggesting that the broad associations seen between BMI and metabolite variation has 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.