Engineered Escherichia coli Nissle 1917 Expressing IGF1 and FGF19 Reduce Liver Fat Accumulation and Restore Microbial Equilibrium in a Metabolic Dysfunction-Associated Steatotic Liver Disease Mice Model

Background and objectives: Endocrine dysregulation and intestinal microbiota unbalance are commonly associated with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the effectiveness of engineered probiotic Escherichia coli Nissle (EcN) 1917 expressing various hormones (IGF1, GLP-1, FGF19, Adiponectin) downregulated in MASLD as a potential therapeutic. Methods: 41 C57BL/6J mice underwent 14 weeks of a high-fat diet intervention for MASLD development. The mice were then separated into seven groups and underwent 7 weeks of probiotic intervention while under the control diet. The mice were grouped as follows: (1) without probiotic; (2) EcN without hormone expression; (3–6) EcN expressing IGF1, GLP-1, FGF19, and Adiponectin, respectively; and (7) liraglutide treatment. Liver fat was measured using MRI and the Oil-Red-O staining of liver histological samples. 16s rRNA sequencing was used to investigate the bacterial composition in mice cecum. Results: Mice receiving EcN expressing IGF1, GLP-1, and FGF19 were effective at reducing liver fat accumulation. Microbiota compositions were different between groups, and the microbial communities of mice receiving EcN expressing IGF1 and FGF19 had higher observed richness. Mice receiving EcN-IGF1 had lower abundance of sulfate-reducing bacteria (Desulfobacterota) associated with gut inflammation and higher abundance of butyrate-producing bacteria (Roseburia sp.) and Lactobacillus reuteri. Mice receiving EcN-FGF19 had lower abundance of bacteria associated with intestinal inflammation (Coriobacteriia) and higher abundance of SCFA-producing bacteria (Roseburia sp. and Blautia sp.) and plasma propionate levels. Discussion: EcN expressing IGF1 and FGF19 have the potential to reduce liver fat accumulation and restore microbial equilibrium. This may be a combined effect of hormones and EcN, as a probiotic, thereby improving gut endocrine and immune functions.