背景:高脂肪饮食会导致肠道生态失调并促进甘油三酯积累,肥胖,肠道通透性变化,炎症,和胰岛素抵抗。可可脂和鱼油都被认为是健康饮食的一部分。然而,它们对饲喂高浓度这些脂肪的小鼠肠道微生物组扰动的不同影响,在没有蔗糖的情况下,还有待阐明。该研究的目的是测试小鼠的无蔗糖可可脂基高脂饮食(C-HFD)是否会导致肠道菌群失调,并伴有以肝性脂肪变性为标志的病理表型。低度炎症,扰动的葡萄糖稳态,和胰岛素抵抗,与饲喂基于鱼油的高脂肪饮食(F-HFD)的对照小鼠相比。
结果:C57BL/6小鼠(5-6只小鼠/组)饲喂两种高脂饮食(C-HFD和F-HFD)24周。两组之间的肝脏重量或总体重没有显着差异。肠道细菌样本的16SrRNA测序显示了C-HFD组的肠道菌群失调,具有差异改变的微生物多样性或相对丰度。拟杆菌,Firmicutes,C-HFD组的变形杆菌含量很高,而Verrucomicrobia,酵母菌(TM7),放线菌,在F-HFD组中,Tenericutes更丰富。C-HFD组中的其他分类群包括拟杆菌,Odoribacter,Sutterilla,Firmicutes细菌(AF12),厌氧等离子体,罗斯布里亚,和分布式副杆菌属。C-HFD组的Firmicutes/拟杆菌(F/B)比率增加,与F-HFD组相比,表明肠道菌群失调。C-HFD组的这些肠道细菌变化预测了与脂肪肝疾病和脂肪生成相关,炎症,葡萄糖代谢,和胰岛素信号通路。与它的微生物组转移一致,C-HFD组表现为肝脏炎症和脂肪变性,空腹血糖高,胰岛素抵抗,肝脏从头脂肪生成增加(乙酰辅酶A羧化酶1(Acaca),脂肪酸合成酶(Fasn),硬脂酰辅酶A去饱和酶-1(Scd1),长链脂肪酸家族成员6(Elovl6)的延伸,过氧化物酶体增殖物激活受体γ(Pparg)和胆固醇合成(β-(羟基β-甲基戊二酰辅酶A还原酶(Hmgcr)。观察到关于脂肪酸摄取的非显著差异(分化簇36(CD36),脂肪酸结合蛋白-1(Fabp1)和外排(ATP结合盒G1(Abcg1),C-HFD组的微粒体TG转移蛋白(Mttp),与F-HFD组比较。C-HFD组还显示炎症标志物包括肿瘤坏死因子α(Tnfa)的基因表达增加,C-C基序趋化因子配体2(Ccl2),和白细胞介素-12(Il12),以及肝纤维化的趋势。
结论:这些发现表明,小鼠无蔗糖的C-HFD喂养可诱导与肝脏炎症相关的肠道菌群失调,脂肪变性,葡萄糖耐受不良和胰岛素抵抗。
BACKGROUND: High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD).
RESULTS: C57BL/6 mice (5-6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. Bacteroidetes, Firmicutes, and Proteobacteria were highly abundant in C-HFD group, while the Verrucomicrobia, Saccharibacteria (TM7), Actinobacteria, and Tenericutes were more abundant in F-HFD group. Other taxa in C-HFD group included the Bacteroides, Odoribacter, Sutterella, Firmicutes bacterium (AF12), Anaeroplasma, Roseburia, and Parabacteroides distasonis. An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (Acaca), Fatty acid synthase (Fasn), Stearoyl-CoA desaturase-1 (Scd1), Elongation of long-chain fatty acids family member 6 (Elovl6), Peroxisome proliferator-activated receptor-gamma (Pparg) and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (Hmgcr). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (CD36), Fatty acid binding protein-1 (Fabp1) and efflux (ATP-binding cassette G1 (Abcg1), Microsomal TG transfer protein (Mttp) in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (Tnfa), C-C motif chemokine ligand 2 (Ccl2), and Interleukin-12 (Il12), as well as a tendency for liver fibrosis.
CONCLUSIONS: These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance.