The Metabolite Indole‐3‐Acetic Acid of Bacteroides Ovatus Improves Atherosclerosis by Restoring the Polarisation Balance of M1/M2 Macrophages and Inhibiting Inflammation

Emerging research has highlighted the significant role of the gut microbiota in atherosclerosis (AS), with microbiota-targeted interventions offering promising therapeutic potential. A central component of this process is gut-derived metabolites, which play a crucial role in mediating the distal functioning of the microbiota. In this study, a comprehensive microbiome-metabolite analysis using fecal and serum samples from patients with atherosclerotic cardiovascular disease and volunteers with risk factors for coronary heart disease and culture histology is performed, and identified the core strain Bacteroides ovatus (B. ovatus). Fecal microbiota transplantation experiments further demonstrated that the gut microbiota significantly influences AS progression, with B. ovatus alone exerting effects comparable to volunteer feces from volunteers. Notably, B. ovatus alleviated AS primarily by restoring the intestinal barrier and enhancing bile acid metabolism, particularly through the production of indole-3-acetic acid (IAA), a tryptophan-derived metabolite. IAA inhibited the TLR4/MyD88/NF-κB pathway in M1 macrophages, promoted M2 macrophage polarisation, and restored the M1/M2 polarisation balance, ultimately reducing aortic inflammation. These findings clarify the mechanistic interplay between the gut microbiota and AS, providing the first evidence that B. ovatus, a second-generation probiotic, can improve bile acid metabolism and reduce inflammation, offering a theoretical foundation for future AS therapeutic applications involving this strain.