Mechanism of Simvastatin and Levocarnitine in Improving Hyperlipidemic Oligoasthenospermia Based on Gut Microbiota and the HPG Axis

OBJECTIVE To investigate the ameliorative effects of the simvastatin(SIM) and levocarnitine(LC) on gut microbiota and hypothalamic-pituitary-gonadal(HPG) axis imbalance and semen quality in hyperlipidemic rats.

METHODS Forty SD rats were randomly divided into normal control group(NC), high-fat diet group(HFD), simvastatin intervention group(SIM), and the levocarnitine intervention group(LC), with 10 rats in each group. The HFD, SIM, and LC groups were fed with a high-fat diet for 4 weeks to establish the hyperlipidemia model. The SIM and LC groups were intragastrically administered with corresponding drugs for 4 weeks. Subsequently, the differences in blood lipids levels, inflammatory factors, oxidative stress indicators, organ coefficients, sex hormones, testicular pathological sections, gut microbiota, and semen quality were compared among the 4 groups.

RESULTS Compared with the NC group, the HFD group showed abnormal blood lipids, and serum total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol(LDL-C) were were significantly increased(P<0.01). Meanwhile, the inflammatory factors including C-reactive protein(CRP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were significantly increased(P<0.05 or P<0.01). The oxidative stress index malondialdehyde(MDA) was increased(P<0.05), while the activity of total superoxide dismutase(T-SOD) was decreased. The contents of HPG axis-related luteinizing hormone(LH), follicle-stimulating hormone(FSH) and testosterone(T) were reduced(P<0.05 or P<0.01). At the phylum level of gut microbiota, the proportions of Firmicutes, Actinobacteria, and Proteobacteria were increased, whereas those of Bacteroidetes, Spirochaetes, and Campylobacterota were decreased. At the genus level, the abundances of Ligilactobacillus, Romboutsia_B were upregulated, while the abundance of Lactobacillus was downregulated. Meanwhile, the testicular and epididymal coefficients were decreased(P<0.01), sperm progressive motility(PR) was reduced(P<0.05), the sperm immobility rate was elevated(P<0.05), and the numbers of interstitial cells and spermatogenic cells were declined(P<0.05). It indicated that a high-fat diet could induce dyslipidemia, inflammatory response, oxidative stress imbalance and gut microbiota disorder, inhibit the function of the HPG axis, and further lead to testicular injury and declined semen quality. Compared with the HFD group, the levels of TC, TG and LDL-C were decreased, MDA content was reduced and T-SOD activity was significantly elevated in SIM and LC groups(P<0.01), accompanied by increased levels of LH, FSH and T related to the HPG axis. The CRP level was significantly decreased in the LC group(P<0.05), while the expression levels of IL-6, CRP and TNF-α were reduced in the SIM group. At the phylum level of gut microbiota: the abundances of Spirochaetes and Verrucomicrobia were increased, while those of Firmicutes, Bacteroidetes and Actinobacteria were decreased in the SIM group. In the LC group, the abundance of Spirochaetes was upregulated, and the abundances of Bacteroidetes, Actinobacteria and Proteobacteria were downregulated. At the genus level, the abundances of beneficial bacteria such as Lactobacillus and Akkermansia were increased and harmful bacteria were decreased in both SIM and LC groups; meanwhile, the abundance of Prevotella was elevated in the LC group. In both groups, the testicular and epididymal coefficients were increased, PR was improved, the sperm immobility rate was reduced, and the quantities of interstitial cells and spermatogenic cells were increased(P<0.05). It was suggested that SIM and LC could restore HPG axis activity and improve reproductive function via 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. SIM and LC have a certain therapeutic effect. Targeted regulation of specific gut microbiota is expected to become a novel therapeutic strategy through multi-pathway synergistic effects.