Abstract 4354717: Specific Microbial Metabolite Enhances the Anti-Atherosclerotic Efficacy of Colchicine by Improving Bioavailability

Abstract

Background: Long-term, low-dose oral administration of colchicine has demonstrated potential in reducing atherosclerotic cardiovascular events, though its efficacy remains controversial due to mixed clinical outcomes. A substantial interindividual variability (20%-80%) in the oral bioavailability of colchicine has been observed, yet the underlying mechanisms are unclear. Here, we investigated whether gut microbiota and its metabolites influence colchicine’s anti-atherosclerotic effects and pharmacokinetics. Methods: ApoE -/- mice fed a high-fat/high-cholesterol diet underwent gut microbiota depletion via antibiotic cocktail (ABX) treatment or replacement via fecal microbiota transplantation (FMT). Mice received a daily oral gavage of colchicine (0.1 mg/kg) or vehicle. At the endpoint of the study, blood, cecal contents, liver and aorta samples were collected. Gut microbiome was analyzed by shotgun metagenomic sequencing, while circulating and intestinal metabolite profiles were quantified using LC-MS/MS-based Q500 kit. The concentrations of colchicine were determined by LC-MS/MS. Results: Colchicine reduced the aortic plaque area by 42% in mice. ABX-induced microbiota depletion abolished the beneficial effects of colchicine, and decreased hepatic colchicine levels while increasing drug retention in cecal content. FMT from colchicine-treated donors did not independently reduce atherosclerosis but significantly enhanced the anti-atherosclerotic effect of colchicine in recipient mice, compared to FMT from vehicle-treated donors. These findings suggest that gut microbiota is essential for colchicine’s therapeutic action and that specific microbial communities can augment its efficacy. Metagenomic and metabolomic analyses showed that colchicine treatment induced enrichment of Hungatella hathewayi and elevated gut levels of its metabolite. Intervention studies revealed that specific metabolite enhanced intestinal absorption and hepatic accumulation of colchicine. Mechanistically, colchicine reduced plaque burden by regulating the hepatic NRF2-GDF15-SHP-1 signaling pathway. Conclusion: The gut microbiota critically regulates colchicine’s anti-atherosclerotic efficacy. Specific microbial metabolite enhances colchicine’s therapeutic effects by increasing its intestinal absorption and bioavailability, thereby potentiating the anti-atherosclerotic action in mice. Ongoing studies aim to validate these findings in clinical cohorts.