High-Resolution Untargeted Metabolomics Reveals Alternate-Day Fasting May Attenuate Diabetic Kidney Disease Progression in BTBR ob/ob Mice by Affecting the HCA, IPA and Reducing Inflammation

Diabetic kidney disease (DKD) is one of the most severe complications of diabetes mellitus, with limited effective therapeutic interventions. Alternate-day fasting (ADF) shows potential in treating DKD, though its mechanisms are not fully understood. In this study, BTBR ob/ob mice underwent 12 weeks of ADF, and high-resolution untargeted metabolomics were performed to uncover the underlying mechanisms. After 12 weeks of ADF, the BTBR ob/ob mice exhibited weight loss, lower blood glucose and LDL-C levels, reduced 24-h urinary protein excretion, and decreased renal collagen deposition. A total of 44 metabolites were differentially expressed, with 25 up-regulated and 19 down-regulated. Notably, hyocholic acid (HCA) and indole-3-propionic acid (IPA), both products of intestinal bacteria, can modulating inflammation were differentially expressed. Furthermore, the kidneys of BTBR ob/ob mice showed significantly lower NF-κB pathway activity and reduced inflammation after 12 weeks of ADF. This study indicates that ADF may alleviate DKD progression by modulating HCA, IPA, and decreasing inflammation.