A randomized, placebo-controlled, crossover trial in 37 individuals with overweight or obesity found that 8 weeks of resistant starch (RS) supplementation led to significant weight loss (mean -2.8 kg) and improved insulin resistance. RS altered gut microbiota composition, with Bifidobacterium adolescentis playing a key role in reducing obesity. Mechanistically, RS-induced changes in gut microbiota altered bile acid profiles, reduced inflammation by restoring the intestinal barrier, and inhibited lipid absorption. These findings suggest that RS may facilitate weight loss through B. adolescentis and that gut microbiota is essential for RS's therapeutic effects. The study highlights the importance of gut microbiota in obesity and metabolic health. Previous research has shown that gut microbiota influences inflammation, fat storage, and glucose metabolism. While fecal microbiota transplantation (FMT) from healthy donors to individuals with obesity showed inconsistent results, combining dietary intervention with FMT can lead to favorable microbiota changes and improved clinical outcomes. Prebiotics, including RS, increase beneficial gut bacteria such as Bifidobacterium and Lactobacillus, which reduce pathogen populations and improve gut barrier function. RS, a fermentable dietary fiber, is not digested by human amylases in the small intestine and is fermented by gut microbiota in the colon. Studies in rodents showed that RS reduced total body fat, particularly visceral fat, compared to digestible starch. However, human data showed no significant impact on body weight after 4–12 weeks of RS consumption. Low-fat diets supplemented with RS had beneficial effects, but high-fat diets reduced RS fermentation and its benefits. This may explain why RS had no significant impact on body weight in clinical trials, as compliance with the diet was low. The study used a crossover trial to investigate the effect of RS as a dietary supplement on obesity and other metabolic phenotypes. Metagenomics and metabolomics analyses showed that RS altered gut microbiota composition and function. RS-modified gut microbiota transferred from human donors to antibiotic-treated mice reduced adiposity and improved glucose metabolism. The study also explored the mechanisms underlying the metabolic advantages conferred by gut microbiota through RS. RS intervention significantly reduced body weight, fat mass, and waist circumference. It improved glucose tolerance and insulin sensitivity, with significant increases in serum adiponectin levels. RS also reduced levels of pro-inflammatory cytokines such as TNFα and IL-1β, and increased levels of ANGPTL4, a potential connection between gut and lipid metabolism. These results suggest that RS may reduce lipid absorption from the diet. RS intervention reshaped gut microbiota, with B. adolescentis, B. longum, and Ruminococcus bromii significantly increased, while other species decreased. B. adolescentis was strongly correlated with lower BMI, waist circumference, and visceral fat. The study also identified that RS-altered gut microbiota increased the production of secondary bile acids, which may alleviateA randomized, placebo-controlled, crossover trial in 37 individuals with overweight or obesity found that 8 weeks of resistant starch (RS) supplementation led to significant weight loss (mean -2.8 kg) and improved insulin resistance. RS altered gut microbiota composition, with Bifidobacterium adolescentis playing a key role in reducing obesity. Mechanistically, RS-induced changes in gut microbiota altered bile acid profiles, reduced inflammation by restoring the intestinal barrier, and inhibited lipid absorption. These findings suggest that RS may facilitate weight loss through B. adolescentis and that gut microbiota is essential for RS's therapeutic effects. The study highlights the importance of gut microbiota in obesity and metabolic health. Previous research has shown that gut microbiota influences inflammation, fat storage, and glucose metabolism. While fecal microbiota transplantation (FMT) from healthy donors to individuals with obesity showed inconsistent results, combining dietary intervention with FMT can lead to favorable microbiota changes and improved clinical outcomes. Prebiotics, including RS, increase beneficial gut bacteria such as Bifidobacterium and Lactobacillus, which reduce pathogen populations and improve gut barrier function. RS, a fermentable dietary fiber, is not digested by human amylases in the small intestine and is fermented by gut microbiota in the colon. Studies in rodents showed that RS reduced total body fat, particularly visceral fat, compared to digestible starch. However, human data showed no significant impact on body weight after 4–12 weeks of RS consumption. Low-fat diets supplemented with RS had beneficial effects, but high-fat diets reduced RS fermentation and its benefits. This may explain why RS had no significant impact on body weight in clinical trials, as compliance with the diet was low. The study used a crossover trial to investigate the effect of RS as a dietary supplement on obesity and other metabolic phenotypes. Metagenomics and metabolomics analyses showed that RS altered gut microbiota composition and function. RS-modified gut microbiota transferred from human donors to antibiotic-treated mice reduced adiposity and improved glucose metabolism. The study also explored the mechanisms underlying the metabolic advantages conferred by gut microbiota through RS. RS intervention significantly reduced body weight, fat mass, and waist circumference. It improved glucose tolerance and insulin sensitivity, with significant increases in serum adiponectin levels. RS also reduced levels of pro-inflammatory cytokines such as TNFα and IL-1β, and increased levels of ANGPTL4, a potential connection between gut and lipid metabolism. These results suggest that RS may reduce lipid absorption from the diet. RS intervention reshaped gut microbiota, with B. adolescentis, B. longum, and Ruminococcus bromii significantly increased, while other species decreased. B. adolescentis was strongly correlated with lower BMI, waist circumference, and visceral fat. The study also identified that RS-altered gut microbiota increased the production of secondary bile acids, which may alleviate