Intermittent Fasting Improves Glucose Metabolism Disorders Induced by High-fat Diet through Modulation of Gut Microbiota and Serum Metabolism in Middle-aged Mice

Abstract Background Intermittent fasting (IF) has received wide attention as an effective diet strategy. Existing studies shown that IF is a promising approach for weight control, improving insulin sensitivity and reducing type 2 diabetes (T2D) prevalence. Methods Twenty-eight 8-month-old male C57BL/6J mice were randomly divided into a normal control group (NC), a high-fat diet group (HF) and an IF group. Body weight (BW) and food intake were monitored weekly. After 20 weeks the intraperitoneal glucose tolerance test (IPGTT), oral glucose tolerance test (OGTT), and intraperitoneal insulin tolerance test (IPITT) were performed weekly in sequence. Fresh faeces were collected to examine changes in gut microbiota, and untargeted metabolite profiling was conducted on serum samples. Results IF significantly reduced weight gain in middle-aged mice fed a high-fat diet, reduced fat mass and liver weight, and improved glucose tolerance and insulin sensitivity. 16S rRNA gene sequencing revealed that IF significantly reduced the Firmicutes/Bacteroidetes (F/B) ratio by increased Muribaculaceae, Bacteroides, Parabacteroides, and decreased Bilophila, Colidextribacter, Oscillibacter. Spearman's correlation analysis indicated that these bacteria were strongly correlated with obesity-related parameters and serum metabolites such as capryloylglycine, N-acetylglycine, 4-ethyl-6-[(3E)-2-ethyl-3-hexen-1-yl]-6-methyl-1,2-dioxan-3-yl acetic acid, etc. Conclusion IF improves glucose metabolism, regulates gut microbiota, and alters serum metabolites. This provides a new pathway for trials testing diabetes prevention in middle-aged and elderly patients.