Consumption of sweeteners and sweetness enhancers (S&SEs) is a popular

strategy to reduce sugar intake, but the role of S&SEs in body weight

regulation and gut microbiota composition remains debated. Here, we

show that S&SEs in a healthy diet support weight loss maintenance and

beneficial gut microbiota shifts in adults with overweight or obesity. In

this multi-centre, randomized, controlled trial, we included 341 adults

and 38 children with overweight or obesity. Adults followed a 2-month

low-energy diet for ≥5% weight loss, followed by a 10-month healthy ad

libitum diet with <10% energy from sugars. One group replaced sugar-rich

products with S&SE products (S&SEs group), while the other did not (sugar

group). Primary outcomes included changes in body weight and gut

microbiota composition at 1 year. Secondary outcomes included changes

in cardiometabolic parameters. The S&SEs group, compared to the sugar

group, maintained greater weight loss at 1 year (1.6 ± 0.7 kg, P = 0.029) and

exhibited distinct gut microbiota shifts, with increased short-chain fatty

acid and methane-producing taxa (q ≤ 0.05). No significant differences were

observed in cardiometabolic markers or in children. Overall, our findings

indicate that prolonged consumption of S&SEs in a healthy diet is a safe

strategy for obesity management. ClinicalTrial.gov identifier: NCT04226911.