Green Alga Enteromorpha prolifera Oligosaccharide Ameliorates Ageing and Hyperglycemia through Gut–Brain Axis in Age‐Matched Diabetic Mice

Scope To investigate the anti‐ageing and anti‐diabetic effects of Enteromorpha prolifera oligosaccharide (EPO) in age‐matched streptozocin‐induced diabetic mice. Methods and Results LC‐MS metabolomics and 16S rRNA sequencing is used to identify the brain metabolites and gut microbiota, respectively. EPO could significantly improve glucose metabolism and activity of total superoxide dismutase in serum. It also could regulate the tricarboxylic acid cycle, arginine, and inosine‐related metabolic pathways in the brain of aged diabetic mice. Inosine is found to enhance the relative expressions of daf‐2, daf‐16, and skn‐1 in insulin‐resistant Caenorhabditis elegans . Additionally, EPO could alter the composition and diversity of gut microbiota in mice. It could upregulate the Signal Transducer and Activator of Transcription 3/Forkhead Box O1 (FOXO1)/B cell lymphoma 6 (Bcl‐6) pathways in the brain and the c‐Jun N‐terminal Kinase (JNK)/FOXO1/Bcl‐6 signaling axis in the intestine to regulate glucose metabolite status and ageing in mice. EPO could also improve the levels of glucagon‐like peptide type 1 (GLP1) expression in the gut, thereby inducing high expression of GLP1 receptor in the brain to control glucose metabolites through the brain–gut axis. Enterococcus is negatively correlated with AMP in the brain and could be a potential hallmark species in age‐related diabetes. Conclusions These results suggest that EPO could be a potential novel natural drug for the treatment of diabetes in the elderly.