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 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 , and . 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 , 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.