The effect of aldafermin expressing-Escherichia coli Nissle 1917 along with dietary change on visceral adipose tissue in MASLD mouse model

Background: Visceral adipose tissue (VAT) accumulation in obesity has been implicated as a key factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Apart from lifestyle change interventions, there is no effective therapy against MASLD. In this study, the effect of a novel microbial therapy along with dietary change on VAT and VAT-liver crosstalk was evaluated in a MASLD mouse model. Methods: MASLD was induced by feeding eighteen C57BL/6J male mice with the American Lifestyle-Induced Obesity diet for fourteen weeks. Subsequently, during the following seven weeks, all mice were switched to standard diet and the intervention group received single gelatine cubes containing 10⁹ CFU each of aldafermin-expressing Escherichia coli Nissle (EcNA, n = 6); while the control groups received either 10⁹ CFU/gelatine cube of non-modified Escherichia coli Nissle (EcN, n = 6) or gelatin cube with no treatment (CTRL, n = 6). The effect of EcNA on epididymal visceral adipose tissue (eVAT) morphology was evaluated by histology and the gene expression profile in eVAT and liver by RNA-sequencing analysis. Results: After seven weeks of intervention, EcNA, when compared to CTRL group, induced smaller adipocytes (p-value = 0.0217 for diameter, p-value = 0.0386 for area). Gene Set Enrichment Analysis in eVAT showed significant upregulation of fatty acid metabolism (FDR-adjusted p-value = 0.001), oxidative phosphorylation (FDR-adjusted p-value < 2.2e-16), peroxisome (FDR-adjusted p-value = 0.0185), and thermogenesis (FDR-adjusted p-value = 0.0199) pathways when EcNA was compared to EcN group. In addition, the impact of EcNA in eVAT-liver gene expression crosstalk was underlined by the upregulation of Bcl6 and Cnst expression in both tissues when EcNA was compared to CTRL and EcN groups. Conclusions: These results support the beneficial effects of EcNA, along with dietary change intervention, in obesity-associated MASLD. This microbial therapy could potentially boost the improvements induced by dietary change in eVAT metabolism and its crosstalk with the liver. (Figure presented.)