Inflammatory bowel disease (IBD) encompasses a group of chronic relapsing disorders which include ulcerative colitis (UC) and Crohn's disease (CD). The incidences of IBD and overweight/obesity are increasing in parallel. Here, we investigated alterations in proteomic in serum and metaproteomic in feces of IBD patients with overweight/obesity and aimed to explore the effect of overweight/ obesity on IBD and the underlying mechanism.This prospective observational study (n = 64) comprised 26 health control subjects (HC, 13 with overweight/obesity) and 38 IBD patients (19 with overweight/obesity) at a tertiary hospital. Overweight/obesity was evaluated by body mass index (BMI) and defined as a BMI greater than 24 kg/m2. The comprehensive serum proteomic and fecal metaproteomic analyses were conducted by ultra-performance liquid chromatography-Orbitrap Exploris 480 mass spectrometry.UC and CD presented similar serum molecular profiles but distinct gut microbiota. UC and CD serum exhibited higher levels of cytoskeleton organization- associated and inflammatory response-related proteins than the HC serum. Compared the serum proteome of UC and CD without overweight/obesity, inflammatory response-associated proteins were dramatically decreased in UC and CD with overweight/obesity. Fecal metaproteome identified 66 species in the feces. Among them, Parasutterella excrementihominis was increased in CD compared with that in HC. UC group had a significant enrichment of Moniliophthora roreri, but had dramatically decreased abundances of Alistipes indistinctus, Clostridium methylpentosum, Bacteroides vulgatus, and Schizochytrium aggregatum. In addition, overweight/obesity could improve the microbial diversity of UC. Specifically, the UC patients with overweight/obesity had increased abundance of some probiotics in contrast to those without overweight/obesity, including Parabacteroides distasonis, Alistipes indistincus, and Ruminococcus bromii.This study provided high-quality multi-omics data of IBD serum and fecal samples, which enabled deciphering the molecular bases of clinical phenotypes of IBD, revealing the impacts of microbiota on IBD, and emphasizing the important role of overweight/obesity in IBD.© 2023. The Author(s).