School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland.
School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland.
Mol Metab. 2023 Dec;78:101823. doi: 10.1016/j.molmet.2023.101823. Epub 2023 Oct 14.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease globally, yet no therapies are approved. The effects of Escherichia coli Nissle 1917 expressing aldafermin, an engineered analog of the intestinal hormone FGF19, in combination with dietary change were investigated as a potential treatment for MASLD.
MASLD was induced in C57BL/6J male mice by American lifestyle-induced obesity syndrome diet and then switched to a standard chow diet for seven weeks. In addition to the dietary change, the intervention group received genetically engineered E. coli Nissle expressing aldafermin, while control groups received either E. coli Nissle vehicle or no treatment. MASLD-related plasma biomarkers were measured using an automated clinical chemistry analyzer. The liver steatosis was assessed by histology and bioimaging analysis using Fiji (ImageJ) software. The effects of the intervention in the liver were also evaluated by RNA sequencing and liquid-chromatography-based non-targeted metabolomics analysis. Pathway enrichment studies were conducted by integrating the differentially expressed genes from the transcriptomics findings with the metabolites from the metabolomics results using Ingenuity pathway analysis.
After the intervention, E. coli Nissle expressing aldafermin along with dietary changes reduced body weight, liver steatosis, plasma aspartate aminotransferase, and plasma cholesterol levels compared to the two control groups. The integration of transcriptomics with non-targeted metabolomics analysis revealed the downregulation of amino acid metabolism and related receptor signaling pathways potentially implicated in the reduction of hepatic steatosis and insulin resistance. Moreover, the downregulation of pathways linked to lipid metabolism and changes in amino acid-related pathways suggested an overall reduction of oxidative stress in the liver.
These data support the potential for using engineered microbial therapeutics in combination with dietary changes for managing MASLD.
代谢相关脂肪性肝病（MASLD），以前称为非酒精性脂肪性肝病（NAFLD），是全球最常见的肝脏疾病，但尚无获批的治疗方法。本研究旨在探讨表达aldafermin 的大肠杆菌 Nissle 1917（aldaf 工程菌）联合饮食改变对 MASLD 的潜在治疗作用。
采用美国生活方式诱导肥胖综合征饮食诱导 C57BL/6J 雄性小鼠发生 MASLD，然后切换至标准饲料喂养 7 周。除了饮食改变外，干预组还接受了表达 aldaf 工程菌的基因工程大肠杆菌 Nissle 的治疗，而对照组分别接受了大肠杆菌 Nissle 载体或未治疗。使用自动化临床化学分析仪检测 MASLD 相关的血浆生物标志物。通过组织学和 Fiji（ImageJ）软件的生物成像分析评估肝脂肪变性。还通过 RNA 测序和基于液相色谱的非靶向代谢组学分析评估干预对肝脏的影响。通过将转录组学研究中差异表达的基因与代谢组学结果中的代谢物相结合，利用 Ingenuity 通路分析进行通路富集研究。
与两组对照组相比，aldaf 工程菌联合饮食改变的干预措施降低了体重、肝脂肪变性、血浆天冬氨酸转氨酶和胆固醇水平。转录组学与非靶向代谢组学分析的整合结果表明，氨基酸代谢及其相关受体信号通路的下调可能与肝脂肪变性和胰岛素抵抗的减少有关。此外，脂质代谢相关通路的下调以及氨基酸相关通路的改变提示肝脏氧化应激的整体降低。
这些数据支持使用工程微生物疗法联合饮食改变来治疗 MASLD 的潜力。
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