基于“肠道菌群-HPG轴”探讨辛伐他汀与左卡尼汀改善高脂血症性少弱精症的作用机制

Exploring the mechanism of simvastatin and L-carnitine in improving hyperlipidemia-induced oligoasthenospermia based on the ""Gut Microbiota-HPG Axis""

关键词:  肠道菌群,高脂血症,精液质量,HPG轴

Key words:  Gut microbiota  Hyperlipidemia  Semen quality  HPG axis

摘要:

目的 高脂血症可能通过肠道菌群失调及下丘脑-垂体-性腺轴(HPG轴)抑制损害男性生殖功能,而辛伐他汀与左卡尼汀对该病理过程的调节作用尚不明确。本研究旨在探讨两药对高脂血症大鼠肠道菌群-HPG轴失衡及精液质量的改善效果。方法 本研究将40只SD大鼠分为普通组(NC)、高脂组(HFD)、辛伐他汀干预组(SIM)和左卡尼汀干预组(LC)。其中HFD、SIM、LC组高脂喂养4周,SIM、LC组分别接受对应药物灌胃干预4周,比较四组血脂、炎症因子、氧化应激、脏器系数、性激素、睾丸病理切片、肠道菌群以及精液质量水平的差异。结果 与NC组相比,HFD组血脂异常,TC、TG、LDL-C显著上升。炎症因子CRP、IL-6、TNF-α显著增高,氧化应激指标MDA上升、T-SOD下降。HPG轴相关LH、FSH、T含量降低。肠道菌群门水平上,厚壁菌门、放线菌门、变形菌门比例升高,拟杆菌门、螺旋体门、弯曲杆菌门降低；属水平上,Ligilactobacillus、Romboutsia_B等升高,Lactobacillus等降低。同时,睾丸和附睾系数降低,精子活力(PR)下降、不活动率上升,间质细胞和精子细胞数量减少。表明高脂饮食可引起血脂异常、炎症反应、氧化应激及肠道菌群紊乱,抑制 HPG 轴致睾丸与精子质量受损。相较HFD组,SIM和LC组TC、TG、LDL-C降低。氧化应激指标MDA降低、T-SOD显著升高。HPG轴相关LH、FSH、T上升。LC组CRP显著降低,SIM 组IL-6、CRP、TNF-α降低。肠道菌群门水平SIM组螺旋体门、疣微菌门上升,厚壁菌门、拟杆菌门、放线菌门等下降；LC组螺旋体门等上升,拟杆菌门、放线菌门变形菌门等下降。属水平SIM组和LC组有益菌如Lactobacillus、Akkermansia等上升,有害菌下降；且LC组Prevotella增加。两组睾丸和附睾系数增加,PR升高,精子不活动率降低,间质细胞增加、精子细胞数量增多。提示辛伐他汀与左卡尼汀可能通过降脂、抗炎、抗氧化及重塑肠道菌群恢复HPG轴活性并改善生殖功能。结论 肠道菌群失调可能通过加剧炎症-氧化应激反应及抑制HPG轴功能影响精液质量,辛伐他汀与左卡尼汀有一定的治疗作用,靶向调节特定菌群或可通过多通路协同作用成为治疗新策略。

Abstract:

Objective Hyperlipidemia may impair male reproductive function through gut microbiota dysbiosis and the inhibition of the hypothalamic-pituitary-gonadal (HPG) axis. However, the regulatory effects of simvastatin and levocarnitine on this pathological process remain unclear. This study aimed to investigate the effects of the two drugs on the gut microbiota-HPG axis imbalance and semen quality in hyperlipidemic rats. Methods In this study, 40 Sprague-Dawley (SD) rats were divided into four groups: the normal control group (NC), the high-fat diet group (HFD), the simvastatin intervention group (SIM), and the levocarnitine intervention group (LC). The HFD, SIM, and LC groups were fed a high-fat diet for 4 weeks. Then, the SIM and LC groups were given corresponding drugs by gavage for another 4 weeks. The differences in blood lipids, inflammatory factors, oxidative stress indices, organ coefficients, sex hormones, testicular pathological sections, gut microbiota, and semen quality levels were compared among the four groups. Results Compared with the NC group, the HFD group had abnormal blood lipids, with significantly increased total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol (LDL-C). The inflammatory factors, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), were significantly increased. The oxidative stress index malondialdehyde (MDA) increased, and total superoxide dismutase (T-SOD) decreased. The contents of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) related to the HPG axis decreased. At the phylum level of gut microbiota, the proportions of Firmicutes, Actinobacteria, and Proteobacteria increased, while those of Bacteroidetes, Spirochaetes, and Campylobacterota decreased. At the genus level, Ligilactobacillus, Romboutsia_B, etc. increased, while Lactobacillus, etc. decreased. Meanwhile, the coefficients of the testis and epididymis decreased, sperm progressive motility (PR) declined, the immobility rate increased, and the numbers of interstitial cells and spermatogenic cells decreased. This indicates that a high-fat diet can lead to abnormal blood lipids, inflammatory response, oxidative stress, and gut microbiota disorder, and inhibit the HPG axis, resulting in damage to the quality of the testis and sperm.Compared with the HFD group, TC, TG, and LDL-C in the SIM and LC groups decreased. The oxidative stress index MDA decreased, and T-SOD increased significantly. LH, FSH, and T related to the HPG axis increased. CRP in the LC group decreased significantly, and IL-6, CRP, and TNF-α in the SIM group decreased. At the phylum level of gut microbiota, Spirochaetes and Verrucomicrobia in the SIM group increased, while Firmicutes, Bacteroidetes, Actinobacteria, etc. decreased. In the LC group, Spirochaetes, etc. increased, and Bacteroidetes, Actinobacteria, Proteobacteria, etc. decreased. At the genus level, beneficial bacteria such as Lactobacillus and Akkermansia in both the SIM and LC groups increased, and harmful bacteria decreased. Moreover, Prevotella increased in the LC group. In both groups, the coefficients of the testis and epididymis increased, PR increased, the sperm immobility rate decreased, and the numbers of interstitial cells and spermatogenic cells increased. It is suggested that simvastatin and levocarnitine may restore the activity of the HPG axis and improve reproductive function through lipid-lowering, anti-inflammatory, antioxidant effects, and gut microbiota remodeling. Conclusion Gut microbiota dysbiosis may affect semen quality by exacerbating the inflammatory-oxidative stress response and inhibiting the function of the HPG axis. Simvastatin and levocarnitine have a certain therapeutic effect. Targeted regulation of specific gut microbiota may become a new therapeutic strategy through the synergistic action of multiple pathways.