Association of lipid-lowering drugs with gut microbiota: A Mendelian randomization study

BACKGROUND: The gut microbiota can be influenced by lipid metabolism. We aimed to evaluate the impact of lipid-lowering medications, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, Niemann-Pick C1-Like 1 protein (NPC1L1) inhibitors, and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors, on gut microbiota through drug target Mendelian randomization (MR) investigation. METHODS: We used genetic variants that were associated with low-density lipoprotein cholesterol (LDL-C) in genome-wide association studies and located within or near drug target genes as proxies for lipid-lowering drug exposure. In addition, expression trait loci in drug target genes were used as complementary genetic tools. We used effect estimates calculated using inverse variance weighted MR (IVW-MR) and summary data-based MR (SMR). Multiple sensitivity analyses were performed. RESULTS: Genetic proxies for lipid-lowering drugs broadly affected the abundance of gut microbiota. High expression of NPC1L1 was significantly associated with an increase in the genus Eggerthella ( 9 = 1.357, SE = 0.337, P = 5.615 x 10-5 ). An HMGCR-mediated increase in LDL-C was significantly associated with the order Pasteurellales ( 9 = 0.489, SE = 0.123, P = 6.955 x 10-5 ) and the genus Haemophilus ( 9 = 0.491, SE = 0.125, P = 8.379 x 10-5 ), whereas a PCSK9-mediated increase in LDL-C was associated with the genus Terrisporobacter (beta = 0.666, SE = 0.127, P = 1.649 x 10-5). No pleiotropy was detected. CONCLUSIONS: This drug target MR highlighted the potential interventional effects of lipid-lowering drugs on the gut microbiota and separately revealed the possible effects of different types of lipid- lowering drugs on specific gut microbiota.