Intestinal Bacterium Akkermansia muciniphila Inhibits Progression of Abdominal Aortic Aneurysm

Aims: This study aimed to investigate the potential molecular mechanisms of Akkermansia muciniphila (Akk) in the treatment of abdominal aortic aneurysm (AAA) through the use of 16S rRNA sequencing and transcriptome sequencing technologies. Results: 16S rRNA sequencing analysis revealed distinct microbial composition in Sham, AAA, and Akk-treated AAA groups, highlighting the key role of Akk. Akk treatment prevented AAA development, reduced extracellular matrix degradation, and suppressed neutrophil extracellular trap (NET) formation. High mobility group box 1 (HMGB1) promoted AAA formation, antagonizing Akk's effects on NETs. Cell studies showed NET-induced ferroptosis in vascular smooth muscle cells (VSMCs), blocked by ferroptosis inhibitor ferrostatin-1, with HMGB1 overexpression enhancing ferroptosis and AMP-activated protein kinase (AMPK) inhibition reversing it. Akk activated AMPK to inhibit ferroptosis, consistent with in vivo results. Innovation: This study combines molecular analyses, cellular experiments, and animal studies to uncover Akk's mechanisms in AAA treatment. Identification of pathways influencing VSMCs' response to NETs and ferroptosis is a significant advancement in vascular biology. Conclusion: Akk mitigates HMGB1-mediated NET formation, activates AMPK to reduce VSMC ferroptosis, and inhibits AAA progression. These findings offer insights into AAA pathogenesis and propose Akk as a potential therapeutic agent for this condition. Antioxid. Redox Signal. 43, 782-804.