Eurotium cristatum Ameliorates Glucolipid Metabolic Dysfunction of Obese Mice in Association with Regulating Intestinal Gluconeogenesis and Microbiome

<i>Eurotium cristatum</i> (EC), a fungus derived from Fu brick tea, exhibits anti-obesity potential, but its mechanisms regulating intestinal gluconeogenesis (IGN) remain unclear. This study aimed to elucidate whether EC alleviates obesity and glucolipid metabolic disorders by modulating the gut microbiota and activating the IGN pathway. The 8-week EC administration at low (10⁴ CFU/mL), medium (10⁶ CFU/mL), and high doses (10⁸ CFU/mL) ameliorated high-fat-diet (HFD)-induced metabolic abnormalities, including aberrant weight gain, dyslipidemia, glucose intolerance and hepatic injury with effects showing a dose-dependent trend. EC treatment significantly activated IGN, as indicated by increased colonic levels of short-chain fatty acids (SCFAs) and succinate (key IGN substrates) and the upregulation of IGN-key enzymes (PEPCK, FBPase, and G6Pase). In addition, EC treatment significantly alleviated the HFD-induced gut dysbiosis by reducing the <i>Firmicutes</i>/<i>Bacteroidetes</i> ratio and enriching beneficial bacteria such as <i>Lachnospiraece_NK4A136_group</i>, <i>Bacteroidota</i> and <i>Alloprevotella</i>. Non-targeted metabolomics analysis revealed that EC significantly altered the linoleic acid metabolism, specifically decreasing the relative levels of bile acid and chenodeoxycholic acid (<i>p</i> < 0.01) while increasing those of linoleic acid and ricinoleic acid (<i>p</i> < 0.05). EC treatment reshaped the gut microbiome, promoted the production of beneficial metabolites (e.g., SCFAs), and consequently activated the IGN pathway, ultimately ameliorating host glucose and lipid metabolic disorders. Our findings provide mechanistic insights into the anti-obesity effects of EC, suggesting its potential for further investigation as a dietary intervention for metabolic diseases.