Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing, PR China (Drs Shi, Zhang, Zhou).
Department of Neurology & Innovation Center for Neurological Disorders , Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, PR China (Dr Liu).
J Clin Lipidol. 2024 Sep-Oct;18(5):e797-e808. doi: 10.1016/j.jacl.2024.05.004. Epub 2024 Jun 5.
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.
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.
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 (β = 1.357, SE = 0.337, P = 5.615 × 10). An HMGCR-mediated increase in LDL-C was significantly associated with the order Pasteurellales (β = 0.489, SE = 0.123, P = 6.955 × 10) and the genus Haemophilus (β = 0.491, SE = 0.125, P = 8.379 × 10), whereas a PCSK9-mediated increase in LDL-C was associated with the genus Terrisporobacter (β = 0.666, SE = 0.127, P = 1.649 × 10). No pleiotropy was detected.
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.
肠道微生物群可受脂代谢影响。我们旨在通过药物靶点孟德尔随机化（MR）研究来评估降脂药物（如前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）抑制剂、尼曼-匹克 C1 样 1 蛋白（NPC1L1）抑制剂和 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR）抑制剂）对肠道微生物群的影响。
我们使用与全基因组关联研究中的低密度脂蛋白胆固醇（LDL-C）相关的遗传变异，并将其作为降脂药物暴露的替代物，这些变异位于药物靶点基因内或附近。此外，还使用药物靶点基因中的表达特征基因座作为补充遗传工具。我们使用基于逆方差加权 MR（IVW-MR）和汇总数据 MR（SMR）计算的效应估计值。进行了多种敏感性分析。
降脂药物的遗传替代物广泛影响了肠道微生物群的丰度。NPC1L1 的高表达与 Eggerthella 属的增加显著相关（β=1.357，SE=0.337，P=5.615×10）。HMGCR 介导的 LDL-C 增加与巴氏杆菌目（β=0.489，SE=0.123，P=6.955×10）和嗜血杆菌属（β=0.491，SE=0.125，P=8.379×10）显著相关，而 PCSK9 介导的 LDL-C 增加与 Terrisporobacter 属（β=0.666，SE=0.127，P=1.649×10）显著相关。未检测到 pleiotropy。
该药物靶点 MR 强调了降脂药物对肠道微生物群的潜在干预作用，并分别揭示了不同类型的降脂药物对特定肠道微生物群的可能影响。
