Early Plasma Proteome Remodeling After Sleeve Gastrectomy in Severe Obesity: A Paired Longitudinal Study with a Non-Obese Reference

Background/Objectives: Circulating proteomic changes after metabolic and bariatric surgery are often described without reference to a non-obese population. We characterized plasma-proteome remodeling following sleeve gastrectomy (SG) using a three-state reference-aware framework. Methods: This exploratory observational analysis included 61 plasma specimens from 49 participants: 26 preoperative (T0), 15 postoperative follow-up (FW), and 20 non-obese control specimens. Twelve surgical participants had matched T0–FW specimens (median sampling interval, 141 days; IQR, 114–193 days; range, 82–219 days). We assessed 408 protein groups using participant-blocked limma analysis and secondary age- and sex-adjusted reference contrasts. Results: Twenty-five proteins changed within participants (Benjamini–Hochberg q < 0.05; 15 increased and 10 decreased). Descriptive reference-aware categories were postoperative-emergent (20), reference-directed attenuation (3), reference-crossing (1), and paired-only (1). A post hoc reference-deviation score calculated from 400 complete-case proteins increased in all 12 matched participants (mean paired change, +0.165; exact sign-flip p = 0.000488). No Reactome pathway remained robust across sensitivity analyses. Conclusions: During the variable postoperative period, proteomic remodeling was heterogeneous and did not uniformly converge toward the non-obese statistical reference. These exploratory associations do not establish surgery-specific effects, clinical biomarker validity, or adverse health consequences.