Gut microbiota dysbiosis-derived macrophage pyroptosis causes polycystic ovary syndrome via steroidogenesis disturbance and apoptosis of granulosa cells
Gut microbiota dysbiosis-derived macrophage pyroptosis causes polycystic ovary syndrome via steroidogenesis disturbance and apoptosis of granulosa cells
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肠道微生物区系失调引起的巨噬细胞焦虑症通过类固醇激素合成障碍和颗粒细胞凋亡导致多囊卵巢综合征
DOI：
10.1016/j.intimp.2022.108717
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发表时间：
2022-03-22
影响因子：
5.6
通讯作者：
Zhou, Chuanchuan
中科院分区：
文献类型：
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作者：
Huang, Jiana;Chen, Peigen;Zhou, Chuanchuan
肠道微生物群失调是多囊卵巢综合征（PCOS）的关键病因。然而，肠道菌群在PCOS发病中的作用机制尚未完全阐明。我们的目的是探讨肠道微生物源性巨噬细胞焦亡在PCOS中的作用。本研究通过脱氢表雄酮（DHEA）诱导PCOS小鼠模型、16 S rDNA测序、蛋白质印迹、基因敲除、转录组和翻译组分析等方法，探讨DHEA诱导PCOS的机制。16 S rDNA测序显示，DHEA诱导的多囊卵巢综合征小鼠肠道阿克曼氏菌减少，革兰氏阴性菌（脱硫弧菌和伯克霍尔德氏菌）丰度升高，并伴有血清脂多糖（LPS）增加。LPS可诱导小鼠卵巢巨噬细胞凋亡，PCOS也可激活巨噬细胞。Gasdermin D（GSDMD）是巨噬细胞凋亡的最终执行者。我们证明了小鼠Gsdmd基因敲除可以显着改善多囊卵巢综合征。从机制上讲，转录组和翻译组分析表明，巨噬细胞焦亡破坏雌激素的产生，促进颗粒细胞凋亡。在PCOS小鼠血清和卵巢中升高的干扰素（IFN）-γ增强了巨噬细胞的焦亡，并加剧了其对颗粒细胞中雌激素受体的影响。令人鼓舞的是，我们发现双硫仑和二甲双胍可以增加肠道阿克曼氏菌的丰度，降低血清IFN-γ水平，抑制卵巢巨噬细胞热凋亡，从而改善多囊卵巢综合征。总的来说，这项研究强调，巨噬细胞pyroptosis，这是由肠道微生物群失调诱导和IFN-γ增强，通过雌激素合成功能障碍和颗粒细胞凋亡在PCOS发病机制中起着关键作用。双硫仑和二甲双胍可提高肠道Akkermansia的丰度并抑制巨噬细胞的焦亡，可被认为是PCOS的潜在治疗策略。
Gut microbiota dysbiosis is critical in the etiology of polycystic ovary syndrome (PCOS). However, the mecha-nisms of gut microbiota in PCOS pathogenesis have not been fully elucidated. We aimed to explore the role of gut microbiota-derived macrophage pyroptosis in PCOS. This study conducted dehydroepiandrosterone (DHEA) induced PCOS mice model, 16S rDNA sequencing, western blot, genetic knocking out, transcriptome and translatome profiling, et al. to evaluate the underlying mechanisms. 16S rDNA sequencing showed reduced gut Akkermansia and elevated gram-negative bacteria (Desulfovibrio and Burkholderia) abundances in DHEA induced PCOS mice, which was accompanied by increased serum lipopolysaccharide (LPS). LPS could induce macrophage pyroptosis in mice ovaries, also activated in PCOS. Gasdermin D (GSDMD) is the final executor of macrophage pyroptosis. We demonstrated that Gsdmd knockout in mice could dramatically ameliorate PCOS. Mechanistically, transcriptome and translatome profiling revealed that macrophage pyroptosis disrupted estrogen production and promoted apoptosis of granulosa cells. Interferon (IFN)-gamma, which was elevated in PCOS mice serum and ovaries, enhanced macrophage pyroptosis and exacerbated its effect on estrogen receptor in granulosa cells. Inspiringly, we identified that disulfiram and metformin could augment gut Akkermansia abundance, reduce serum IFN-gamma level, inhibit macrophage pyroptosis in ovaries, therefore ameliorating PCOS. Collectively, this study emphasizes that macrophage pyroptosis, which was induced by gut microbiota dysbiosis and enhanced by IFN-gamma, plays a key role in PCOS pathogenesis through estrogen synthesis dysfunction and apoptosis of granulosa cells. Disulfiram and metformin, which enhanced gut Akkermansia abundance and suppressed macrophage pyroptosis, may be considered as potential therapeutic strategies for PCOS.