Heat-Processed Diet Rich in Advanced Glycation End Products Induced the Onset and Progression of NAFLD via Disrupting Gut Homeostasis and Hepatic Lipid Metabolism

Epidemiologic studies have suggested an association between the consumption of dietary advanced glycation end products (dAGEs) and the incidence of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism by which dAGEs induce NAFLD development, particularly the pathogenic role of the gut-liver axis, remains poorly understood. In this study, by establishing a high-AGE diet (HAD)-fed C57BL/6 mouse model, we employed multiomics approaches combined with a series of biological analyses to investigate the effect of HAD on NAFLD in vivo. Our results showed that exposure to HAD led to fat accumulation, oxidative stress, inflammation, and fibrosis in the liver of mice. Transcriptome analysis further revealed that HAD exposure disrupted lipid metabolism and activated inflammation-related signaling pathways in the liver. Additionally, exposure to HAD induced perturbations in gut homeostasis, as evidenced by the compromised gut barrier function, reduced probiotic abundance, and increases in pathogenic bacterial proportions. Dysbiosis of gut homeostasis may further act as a trigger for the initiation and progression of NAFLD via the gut-liver axis. This study sheds light on the underlying mechanisms through which dAGEs contribute to the development of NAFLD and helps to understand the detrimental effects of food ultraprocessing products in modern diets. Future studies are needed to explore the in-depth mechanisms related to the gut-liver axis to consolidate our conclusions.