Improvement of Insulin Resistance by Lactobacillus johnsonii-Derived Indole-3-Lactic Acid

Insulin resistance (IR), a primary pathological driver of dysregulated glucose and lipid metabolism, is closely associated with elevated oxidative stress. Gut microbiota contributes to IR via bioactive metabolites. Among these, microbial tryptophan-derived indole compounds have emerged as key metabolic regulators, yet their specific targets remain unclear. In this study, 16S rRNA sequencing and metabolomics analyses indicated that tryptophan metabolism serves as the primary pathway through which Lactobacillus johnsonii Y1 alleviates IR. Genomic analysis of L. johnsonii Y1 and in vitro fermentation experiments subsequently identified indole-3-lactic acid (ILA) as the key functional metabolite. Further experimentation in a cellular IR model demonstrated that ILA restores insulin sensitivity and glucose uptake. Mechanistically, transcriptomic analysis revealed that ILA enhances mitochondrial complex IV (CIV) activity through the upregulation of COX5B, thereby reducing reactive oxygen species production, attenuating inflammation and restoring insulin signaling. Together, these findings highlight an L. johnsonii-derived ILA-CIV axis that alleviates oxidative stress and improves IR, offering a tryptophan-mitochondrial axis-targeted strategy for IR management.