Role of gut microbiota in sex- and diet-dependent metabolic disorders that lead to early mortality of androgen receptor-deficient male mice
Role of gut microbiota in sex- and diet-dependent metabolic disorders that lead to early mortality of androgen receptor-deficient male mice
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DOI：
10.1152/ajpendo.00461.2019
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发表时间：
2020-04-01
影响因子：
5.1
通讯作者：
Yamaji, Ryoichi
中科院分区：
文献类型：
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作者：
Harada, Naoki;Hanada, Kazuki;Yamaji, Ryoichi
肠道微生物群参与男性性成熟后雄激素缺乏诱导的代谢紊乱（迟发性性腺功能减退症）。然而，它在先天性雄激素缺乏症的能量代谢中的作用（例如，雄激素不敏感综合征）仍然难以捉摸。在这里，我们通过给予高脂饮食（HFD）和/或抗生素来检查雄激素受体敲除（ARKO）小鼠中肠道微生物群与代谢疾病症状之间的联系。喂食HFD的雄性ARKO小鼠（而非喂食标准饲料的雄性或喂食HFD的雌性）表现出饲料效率增加、肥胖伴内脏脂肪细胞质量增加和肥大、肝脂肪变性、葡萄糖耐受不良、胰岛素抵抗和大腿肌肉损失。相比之下，皮下脂肪量在ARKO小鼠中积累，与饮食和性别无关。值得注意的是，在ARKO雄性动物中观察到的所有HFD依赖性代谢紊乱在抗生素给药后均消失。ARKO特别降低了喂食HFD的雄性的粪便重量与食物重量和盲肠重量与体重的比率。来自HFD喂养的雄性小鼠的粪便微生物群的16 S rRNA测序揭示了对照和ARKO小鼠之间微生物群组成的差异。几个属或种（例如，Turicibacter和Lactobacillus reuteri）在ARKO小鼠中富集，抗生素治疗破坏了这些变化。此外，HFD喂养的ARKO雄性小鼠的寿命短于对照小鼠，表明雄激素缺乏导致代谢功能障碍，导致过早死亡。这些研究结果还表明，AR信号在预防代谢功能障碍中发挥作用，可能是通过影响肠道微生物组，并提高我们对性腺功能减退和雄激素不敏感受试者健康后果的理解。
The gut microbiota is involved in metabolic disorders induced by androgen deficiency after sexual maturation in males (late-onset hypogonadism). However, its role in the energy metabolism of congenital androgen deficiency (e.g., androgen-insensitive syndrome) remains elusive. Here, we examined the link between the gut microbiota and metabolic disease symptoms in androgen receptor knockout (ARKO) mouse by administering high-fat diet (HFD) and/or antibiotics. HFD-fed male, but not standard diet-fed male or HFD-fed female, ARKO mice exhibited increased feed efficiency, obesity with increased visceral adipocyte mass and hypertrophy, hepatic steatosis, glucose intolerance, insulin resistance, and loss of thigh muscle. In contrast, subcutaneous fat mass accumulated in ARKO mice irrespective of the diet and sex. Notably, all HFD-dependent metabolic disorders observed in ARKO males were abolished after antibiotics administration. The ratios of fecal weight-to-food weight and cecum weight-to-body weight were specifically reduced by ARKO in HFD-fed males. 16S rRNA sequencing of fecal microbiota from HFD-fed male mice revealed differences in microbiota composition between control and ARKO mice. Several genera or species (e.g., Turicibacter and Lactobacillus reuteri, respectively) were enriched in ARKO mice, and antibiotics treatment spoiled the changes. Furthermore, the life span of HFD-fed ARKO males was shorter than that of control mice, indicating that androgen deficiency causes metabolic dysfunctions leading to early death. These findings also suggest that AR signaling plays a role in the prevention of metabolic dysfunctions, presumably by influencing the gut microbiome, and improve our understanding of health consequences in subjects with hypogonadism and androgen insensitivity.