Gut Microbiota Modulation by Lysozyme as a Key Regulator of Vascular Inflammatory Aging

Vascular inflammatory aging is strongly associated with multimorbidity, including immunosenescence. Here, bioinformatic analysis indicated elevated expression of the lysozyme (LYZ) gene in age-dependent vascular diseases. Lyz1 deficiency led to vascular inflammatory aging, including damage to indicators related to oxidative stress, vascular function, and inflammation in the serum and vascular tissues of wild-type (WT) and Lyz1^-/- mice. The 16S ribosomal RNA sequencing of intestinal contents revealed increased Bifidobacterium and its metabolism of acetate, butyrate, omega-muricholic acid, propionate, and valeric acid in Lyz1^-/- mice compared with that in WT mice. Additionally, RNA sequencing of vascular tissues identified differentially expressed genes in Lyz1^-/- mice compared with those in WT mice, as well as enrichment of the common phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. Vascular inflammatory aging phenotypes were detected in the blood vessels of antibiotic-treated and germ-free mice, and the PI3K-Akt signaling pathway was inhibited. Importantly, intravenous LYZ administration worsened the pathological conditions, whereas oral LYZ administration successfully restored the gut microbial balance and reversed the vascular inflammatory aging phenotypes. Collectively, this study establishes LYZ as a novel biomarker for age-related vascular diseases and the gut microbiota-PI3K-Akt axis as a promising therapeutic target.