The substantially increased prevalence of obesity and obesity-related diseases has generated considerable concern. Currently, synthetic biological strategies have played an essential role in preventing and treating chronic diseases such as obesity. A growing number of symbiotic bacteria used as vectors for genetic engineering have been applied to create living therapeutics. In this study, using Bacillus subtilis as a cellular chassis, we constructed the engineered butyrate-producing strain BsS-RS06551 with a butyrate yield of 1.5 g/liter. A mouse model of obesity induced by a high-fat diet (HFD) was established to study the long-term intervention effects of this butyrate-producing bacteria on obesity. Combined with phenotypic assay results, we found that BsS-RS06551 could effectively retard body weight gain induced by a high-fat diet and visceral fat accumulation of mice, whereas it could improve glucose tolerance and insulin tolerance, reducing liver damage. We explored the BsS-RS06551 mechanism of action on host function and changes in intestinal flora by integrating multiple omics profiling, including untargeted metabolomics and metagenomics. The results showed that 24 major differential metabolites were involved in the metabolic regulation of BsS-RS06551 to prevent obesity in mice, including bile acid metabolism, branch chain amino acids, aromatic amino acids, and other metabolic pathways. Continuous ingestion of BsS-RS06551 could regulate gut microbiota composition and structure and enhance intestinal flora metabolic function abundance, which was closely related to host interactions. Our results demonstrated that engineered butyrate-producing bacteria had potential as an effective strategy to prevent obesity. IMPORTANCE Obesity is a chronic metabolic disease with an imbalance between energy intake and energy expenditure, and obesity-related metabolic diseases have become increasingly common. There is an urgent need to develop effective interventions for the prevention and treatment of obesity. This study showed that long-term consumption of BsS-RS06551 had a significant inhibitory effect on obesity induced by a high-fat diet and was more potent in inhibiting obesity than prebiotic inulin. In addition, this study showed a beneficial effect on host glucose, lipid metabolism, and gut microbe composition. Considering its colonization potential, this engineered bacteria provided a new strategy for the effective and convenient treatment of obesity in the long term.
Keywords: butyrate; engineered bacteria; gut microbes; metabolomics; metagenomics; obesity; synthetic biology.