Reshaping of the fecal proteome and metaproteome in obese patients 2 years after bariatric surgery

Bariatric surgery provides effective and durable weight loss in patients with severe obesity. Both the surgical procedure and postoperative management, including dietary and behavioral changes, are known to induce long-term alterations in gut microbiota composition. However, their impact on microbial and host proteome profiles remains poorly understood. In this prospective, multicenter cohort study, we compared the fecal metaproteome profile of 45 patients with severe obesity at preoperative baseline (T0) and 2 years after surgery (T1). Patients were randomized to receive either Roux-en-Y gastric bypass or one anastomosis gastric bypass. At T1, the relative abundance of the bacterial genera Akkermansia, Anaerotignum, Desulfovibrio, Streptococcus, and Veillonella significantly increased, whereas that of Faecalibacterium and Romboutsia decreased. Furthermore, we observed a significant increase in the relative abundance of microbial enzymes involved in glycolysis, short-chain fatty acid biosynthesis, amino acid metabolism, and cofactor/vitamin biosynthesis, alongside various outer membrane proteins encoded by Enterobacterales. Conversely, several proteins involved in oxidative phosphorylation and sporulation were reduced. Moreover, 74 human proteins, primarily associated with immune functions, showed a significant increase in relative abundance at T1, while numerous digestive enzymes displayed a downward trend. Our data reveal that a distinct reshaping of the fecal proteome and metaproteome persists 2 years after bariatric surgery. Future studies are needed to elucidate the mechanistic aspects of host-microbiota interaction and to identify associations with long-term clinical outcomes. IMPORTANCE Bariatric surgery is widely recognized as the most effective and durable intervention for severe obesity; however, its long-term molecular effects on gut microbiota-host interactions remain poorly understood. By applying shotgun metaproteomics to fecal samples collected before and 2 years after surgery, our study provides novel insights into the functional consequences of bariatric bypass procedures. We demonstrate sustained alterations in both microbial and host protein profiles, including metabolic enzymes, outer membrane proteins, and immune-related factors, revealing a long-lasting remodeling of gut ecosystem functions. These findings underscore the value of metaproteomics in uncovering molecular mechanisms underlying bariatric surgery outcomes and may ultimately guide the development of microbiome- or host-targeted strategies to optimize therapy and long-term patient care.