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

Background: 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, kg/m).

Objectives: In this study, we used the Netherlands Epidemiology of Obesity (NEO) study data to identify observational and causal associations between BMI and metabolite response to a liquid meal.

Methods: A liquid meal challenge was performed, and Nightingale Health metabolite profiles were collected in 5744 NEO participants. Observational and one-sample Mendelian randomization (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.

Results: We observed 473 associations with BMI (175 fasting, 188 postprandial, and 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, and 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 (β: -0.081; SE: 0.023; P = 5.91 × 10), suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI.

Conclusions: Overall, this study showed that 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 are detected, and these may likely mark novel life course risk exposures driven by regular nutrition.