Purpose Diabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesityassociated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro-or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients. Methods A randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months. Results There were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [− 1 (95% CI − 4; 3) vs +3 (− 1; 8) cm, synbiotics vs. placebo, respectively, p = 0.04], serum zonulin [− 0.04 (− 0.2; 0.1) vs +0.3 (− 0.05; 0.6) ng/ml, p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (− 1.7; 12.5) vs − 5.0 (− 10.1; 0.2) points, p = 0.02] after 3 months of intervention, and lipoprotein (a) [− 2.1 (− 5.7; 1.6) vs +3.4 (− 0.9; 7.9) mg/dl, p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points. Conclusions Glucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity.