Fish Oil Ameliorates Glycolipid Metabolism Disorders Induced by Long‐Term Potato Chip Diet Through Gut‐Liver Axis

ABSTRACT Fried potatoes are associated with a global rise in metabolic diseases and raise substantial health concerns. However, limited studies have addressed adverse effects of fried potato diets and potential prevention strategies. Here, we aim to uncover detrimental effects of long‐term potato chip consumption on glycolipid metabolism through a 13‐week animal study and evaluate the protective role of fish oil supplementation. Results revealed that potato chip consumption significantly increased body weight, serum and hepatic total cholesterol, blood glucose, and insulin resistance, alongside liver, pancreas, and adipose tissue damage, which was obviously ameliorated by fish oil intervention. Transcriptional analysis revealed that fish oil supplementation mitigated inflammation, gluconeogenesis, and lipid synthesis. Moreover, metagenomics and metabolomics uncovered that fish oil treatment improved gut health by evaluating the abundances of probiotics Bifidobacterium pseudolongum and Lactobacillus johnsonii and raising hepatic docosahexaenoic acid, while reducing hypoxanthine and xanthine. The beneficial effect could be evidenced by showing negative correlations between the abundances of Lactobacillus reuteri and L. johnsonii and hepatic levels of hypoxanthine and xanthine, whereas these bacterial species demonstrated positive correlations with unsaturated fatty acid concentrations. These associations are attributed to the modulative role of fish oil supplementation in the functions of key enzymes, including l ‐lactate dehydrogenase (EC:1.1.1.27) and acetate kinase (EC:2.7.2.1), involved in gluconeogenesis and lipid synthesis through the gut microbiota. In conclusion, these findings highlight the gut–liver axis as a promising target for restoring glycolipid homeostasis and underscore the beneficial role of fish oil use in alleviating unhealthy diet‐induced metabolic disorders.