Heat-Processed\nDiet Rich in Advanced Glycation End\nProducts Induced the Onset and Progression of NAFLD via Disrupting\nGut Homeostasis and Hepatic Lipid Metabolism

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