Baseline metabolomic profile as potential biomarker for weight change after Roux-en-Y gastric bypass (RYGB) surgery

Metabolic and bariatric surgery (MBS) is the most effective intervention for sustained weight loss and cardiometabolic improvement in individuals with severe obesity. However, long-term outcomes vary, with many patients experiencing weight regain. The biological determinants of this variability remain incompletely understood. Given the integrative nature of the metabolome—capturing interactions among host genetics, diet, microbiota, and environmental exposures—we hypothesized that baseline circulating metabolites could stratify individuals into distinct long-term weight trajectory groups. We profiled untargeted fasting plasma metabolites in a nested case-control study within the Longitudinal Assessment of Bariatric Surgery (LABS-2) cohort. From these metabolites, a 13-metabolite risk score (MetRS) predictive of weight regain five years after Roux-en-Y gastric bypass was derived. The MetRS, which captures pathways including fatty acid oxidation, bile acid conjugation, and microbial-host co-metabolism, outperformed clinical variables in predicting long-term weight outcomes. Its performance was evaluated in two independent cohorts, including one assessed a median of seven years post-surgery. Genomic analyses identified common variants in loci including AGXT2 and SLC7A5 associated with key MetRS metabolites, suggesting a heritable component to the observed metabolic signature. Together, these findings lay the groundwork for a clinically actionable framework to identify individuals at risk for weight recidivism and support the integration of metabolic profiling into preoperative assessment for personalized obesity care.