Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome.
Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome.
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DOI：
10.1128/msystems.00020-18
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发表时间：
2018-05
期刊：
影响因子：
6.4
通讯作者：
Haddad GG
中科院分区：
文献类型：
--
作者：
Tripathi A;Melnik AV;Xue J;Poulsen O;Meehan MJ;Humphrey G;Jiang L;Ackermann G;McDonald D;Zhou D;Knight R;Dorrestein PC;Haddad GG
肠道菌群失调会介导与 OSA 共存的各种心血管疾病。为了了解生态失调在 OSA 引起的心血管和代谢疾病中的作用，我们系统地研究了间歇性低氧/高碳酸应激（IHH，模仿 OSA）对动物模型肠道微生物的影响。我们利用纵向研究设计和配对组学来研究肠道中的微生物和分子动力学，以确定微生物对 IHH 肠道代谢的贡献。我们观察到肠道代谢组中微生物依赖性的变化，这将指导未来对肠道微生物与 OSA 合并症之间尚未认识到的机制联系的研究。此外，我们还重点介绍了与 OSA 相关的心血管和代谢疾病的新型非侵入性生物标志物。阻塞性睡眠呼吸暂停（OSA）是一种常见疾病，其特征是睡眠期间上呼吸道塌陷导致呼吸间歇性阻塞。由于间歇性气道阻塞，会出现间歇性低氧（缺氧）和高二氧化碳（高碳酸血症）。尽管有关潜在因果途径的数据仍在不断发展，但 OSA 与不良心血管和代谢结果相关。由于吸入的 O2 和 CO2 的变化会影响肠道微生物群的生态，并且微生物群已被证明会导致各种心脏代谢紊乱，因此我们假设 OSA 会改变肠道生态系统，从而加剧下游的生理后果。在这里，我们使用喂食高脂肪饮食并暴露于间歇性缺氧和高碳酸血症 (IHH) 的 Ldlr−/− 小鼠来模拟人类 OSA 及其心血管后果。对肠道微生物组和代谢组进行了纵向表征（使用 16S rRNA 扩增子测序和非靶向液相色谱-串联质谱 [LC-MS/MS]），并发现 IHH 期间存在共变。微生物组和代谢组数据的联合分析揭示了肠道中微生物（>10%，最显着的是梭状芽胞杆菌）和分子（>22%）物种的显着组成变化。此外，大量改变的分子包括微生物依赖性胆汁酸、肠木脂素和脂肪酸，凸显了 IHH 对肠道中宿主共生生物共代谢的影响。因此，我们提出了 IHH 扰乱肠道微生物组功能的第一个证据，为理解其与心脏代谢疾病的参与奠定了基础。重要性 肠道菌群失调会介导与 OSA 共存的各种心血管疾病。为了了解生态失调在 OSA 引起的心血管和代谢疾病中的作用，我们系统地研究了间歇性低氧/高碳酸应激（IHH，模仿 OSA）对动物模型肠道微生物的影响。我们利用纵向研究设计和配对组学来研究肠道中的微生物和分子动力学，以确定微生物对 IHH 肠道代谢的贡献。我们观察到肠道代谢组中微生物依赖性的变化，这将指导未来对肠道微生物与 OSA 合并症之间尚未认识到的机制联系的研究。此外，我们还重点介绍了与 OSA 相关的心血管和代谢疾病的新型非侵入性生物标志物。
Intestinal dysbiosis mediates various cardiovascular diseases comorbid with OSA. To understand the role of dysbiosis in cardiovascular and metabolic disease caused by OSA, we systematically study the effect of intermittent hypoxic/hypercapnic stress (IHH, mimicking OSA) on gut microbes in an animal model. We take advantage of a longitudinal study design and paired omics to investigate the microbial and molecular dynamics in the gut to ascertain the contribution of microbes on intestinal metabolism in IHH. We observe microbe-dependent changes in the gut metabolome that will guide future research on unrecognized mechanistic links between gut microbes and comorbidities of OSA. Additionally, we highlight novel and noninvasive biomarkers for OSA-linked cardiovascular and metabolic disorders. Obstructive sleep apnea (OSA) is a common disorder characterized by episodic obstruction to breathing due to upper airway collapse during sleep. Because of the episodic airway obstruction, intermittently low O2 (hypoxia) and high CO2 (hypercapnia) ensue. OSA has been associated with adverse cardiovascular and metabolic outcomes, although data regarding potential causal pathways are still evolving. As changes in inspired O2 and CO2 can affect the ecology of the gut microbiota and the microbiota has been shown to contribute to various cardiometabolic disorders, we hypothesized that OSA alters the gut ecosystem, which, in turn, exacerbates the downstream physiological consequences. Here, we model human OSA and its cardiovascular consequence using Ldlr−/− mice fed a high-fat diet and exposed to intermittent hypoxia and hypercapnia (IHH). The gut microbiome and metabolome were characterized longitudinally (using 16S rRNA amplicon sequencing and untargeted liquid chromatography-tandem mass spectrometry [LC-MS/MS]) and seen to covary during IHH. Joint analysis of microbiome and metabolome data revealed marked compositional changes in both microbial (>10%, most remarkably in Clostridia) and molecular (>22%) species in the gut. Moreover, molecules that altered in abundance included microbe-dependent bile acids, enterolignans, and fatty acids, highlighting the impact of IHH on host-commensal organism cometabolism in the gut. Thus, we present the first evidence that IHH perturbs the gut microbiome functionally, setting the stage for understanding its involvement in cardiometabolic disorders. IMPORTANCE Intestinal dysbiosis mediates various cardiovascular diseases comorbid with OSA. To understand the role of dysbiosis in cardiovascular and metabolic disease caused by OSA, we systematically study the effect of intermittent hypoxic/hypercapnic stress (IHH, mimicking OSA) on gut microbes in an animal model. We take advantage of a longitudinal study design and paired omics to investigate the microbial and molecular dynamics in the gut to ascertain the contribution of microbes on intestinal metabolism in IHH. We observe microbe-dependent changes in the gut metabolome that will guide future research on unrecognized mechanistic links between gut microbes and comorbidities of OSA. Additionally, we highlight novel and noninvasive biomarkers for OSA-linked cardiovascular and metabolic disorders.