BackgroundThe gut microbiota has emerged as a potential therapeutic target to improve the management of obesity and its comorbidities.ObjectiveWe investigated the impact of a high fiber (∼38 g/d) plant-based diet, consumedad libitum, with or without added inulin-type fructans (ITF), on the gut microbiota composition and cardiometabolic outcomes in subjects with obesity. We also tested if baselinePrevotella/Bacteroides(P/B) ratio predicts weight loss outcomes.MethodsThis is a secondary exploratory analysis from the PREVENTOMICS study, in which 100 subjects (82 completers) aged 18–65 years with body mass index 27–40 kg/m2were randomized to 10 weeks of double-blinded treatment with a personalized or a generic plant-based diet. Changes from baseline to end-of-trial in gut microbiota composition (16S rRNA gene amplicon sequencing), body composition, cardiometabolic health and inflammatory markers were evaluated in the whole cohort (n= 82), and also compared in the subgroup of subjects who were supplemented with an additional 20 g/d ITF-prebiotics (n= 21) or their controls (n= 22).ResultsIn response to the plant-based diet, all subjects lost weight (−3.2 [95% CI –3.9, −2.5] kg) and experienced significant improvements in body composition and cardiometabolic health indices. Addition of ITF to the plant-based diet reduced microbial diversity (Shannon index) and selectively increasedBifidobacteriumandFaecalibacterium(q< 0.05). The change in the latter was significantly associated with higher values of insulin and HOMA-IR and lower HDL cholesterol. In addition, the LDL:HDL ratio and the concentrations of IL-10, MCP-1 and TNFα were significantly elevated in the ITF-subgroup. There was no relationship between baseline P/B ratio and changes in body weight (r= −0.07,p= 0.53).ConclusionA plant-based diet consumedad libitummodestly decreases body weight and has multiple health benefits in individuals with obesity. Addition of ITF-prebiotics on top this naturally fiber-rich background selectively changes gut microbiota composition and attenuates some of the realized cardiometabolic benefits.Clinical trial registration[https://clinicaltrials.gov/ct2/show/NCT04590989], identifier [NCT04590989].