Limosilactobacillus reuteri with indole-3-lactic acid-producing capacity protects against atherosclerosis by fortifying the gut-vascular barrier

Introduction: The gut microbiota and its metabolites are implicated in atherosclerosis, but the specific effector molecules and their pathophysiological significance remain unclear.
Objectives: This study aimed to identify key atheroprotective microbial metabolites and to elucidate the mechanism by which they confer protection.
Methods: We combined clinical correlation analysis in atherosclerosis patients with interventional studies in ApoE⁻/⁻ mice supplemented with the high ILA-producing probiotic strain Limosilactobacillus reuteri Lr9. Mechanistic insights were gained through integrated vascular proteomics, colon transcriptomics, gut microbiomics, metabolome analysis, and validation in a Caco-2/HUVEC co-culture model of the gut-vascular barrier (GVB).
Results: Serum levels of indole-3-lactic acid (ILA) were significantly reduced in patients and inversely correlated with systemic LPS. Lr9 supplementation attenuated aortic plaque formation, reduced serum LPS, and restored GVB integrity in mice. Multi-omics analysis revealed that Lr9 suppressed pro-inflammatory signaling, upregulated tight junction and autophagy pathways, and remodeled the gut ecosystem by suppressing LPS-producing taxa while enriching beneficial bacteria and protective unsaturated fatty acids. Both Lr9 and its effector ILA directly enhanced barrier function in the GVB model.
Conclusion: Our findings establish ILA as a definitive mediator of atheroprotection and identify the GVB as a critical, therapeutically actionable target. We position L. reuteri Lr9 as a promising next-generation probiotic that acts via the gut-vascular axis to ameliorate disease.