The biological mechanism underlying the association between low body mass index (BMI) and increased risk of esophageal malignancy remains uncertain. We aimed to explore the role of metabolic alterations in the effect of low BMI on esophageal malignancy. We conducted a nested case-control study using a large-scale community-based screening cohort in a high-risk region for esophageal cancer (263 cases and 263 matched controls). Metabolomic profiling was performed based on untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, using the serum samples collected at enrollment prior to cancer diagnosis. Linear regression and conditional logistic regression were used to identify BMI-related metabolites and metabolites associated with esophageal malignancy, respectively, and the shared metabolites were included in mediation analysis. Low BMI was positively associated with esophageal malignancy (odds ratio (OR) = 1.8 (95% confidence interval: 1.1–2.8)). A total of 160 metabolites were identified to be associated with low BMI, and 107 metabolites were associated with esophageal malignancy. Among the 21 shared metabolites, four metabolites (three lipids and one amino acid) were identified as mediators for the association between low BMI and esophageal malignancy, with the mediation effect (OR) of 1.1 for each mediator. The metabolic signature constructed based on these mediators could explain 46.0% of the effect of low BMI on esophageal malignancy. Lipid-dominated metabolites mediate the association between low BMI and esophageal malignancy, which has provided crucial clues for understanding the etiology of esophageal malignancy and selection of early-warning metabolic biomarkers.
Liu et al. (Wed,) studied this question.