Lactiplantibacillus plantarum N1 derived lipoteichoic acid alleviates insulin resistance in association with modulation of the gut microbiota and amino acid metabolism

This study aimed to investigate the effects of heat-killed Lactiplantibacillus plantarum N1 (HK-N1) and lipoteichoic acid (LTA) derived from it on alleviating insulin resistance by modulating the gut microbiota and amino acid metabolism. High-fat diet (HFD)-fed mice were administered live bacteria or HK-N1, and the results demonstrated that HK-N1 significantly reduced epididymal adipocyte size and serum low density lipoprotein-cholesterol, and improved insulin resistance by increasing the YY peptide and glucagon-like peptide levels. HK-N1 also modulated the gut microbiome composition, enhancing microbiota uniformity and reducing the abundance of Ruminococcus, Oscillospira and norank_f_Mogibacteriaceae. Three main active substances obtained from HK-N1 (membrane protein, peptidoglycan, and lipoteichoic acid) were also used to investigate their potential effects in hyperglycemic zebrafish. Only LTA reduced blood sugar and altered the gut microbiome, particularly reducing Aeromonas, which is positively related to hyperglycemia. Untargeted metabolomics revealed that LTA improved vitamin and amino acid metabolism, thereby alleviating metabolic disorders in zebrafish. Collectively, our findings indicate that HK-N1, primarily through LTA, modulated insulin sensitivity by regulating the gut microbiota and amino acid metabolism, offering a potential therapeutic strategy for insulin resistance and type 2 diabetes mellitus.