Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome

ABSTRACT 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...

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Autores principales:	Anupriya Tripathi, Alexey V. Melnik, Jin Xue, Orit Poulsen, Michael J. Meehan, Gregory Humphrey, Lingjing Jiang, Gail Ackermann, Daniel McDonald, Dan Zhou, Rob Knight, Pieter C. Dorrestein, Gabriel G. Haddad
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	cardiovascular metabolism microbiome sleep apnea Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c01326f5b4b0417ba6d9d3532c83605c
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spelling	oai:doaj.org-article:c01326f5b4b0417ba6d9d3532c83605c2021-12-02T18:15:44ZIntermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome10.1128/mSystems.00020-182379-5077https://doaj.org/article/c01326f5b4b0417ba6d9d3532c83605c2018-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00020-18https://doaj.org/toc/2379-5077ABSTRACT 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.Anupriya TripathiAlexey V. MelnikJin XueOrit PoulsenMichael J. MeehanGregory HumphreyLingjing JiangGail AckermannDaniel McDonaldDan ZhouRob KnightPieter C. DorresteinGabriel G. HaddadAmerican Society for Microbiologyarticlecardiovascularmetabolismmicrobiomesleep apneaMicrobiologyQR1-502ENmSystems, Vol 3, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	cardiovascular metabolism microbiome sleep apnea Microbiology QR1-502
spellingShingle	cardiovascular metabolism microbiome sleep apnea Microbiology QR1-502 Anupriya Tripathi Alexey V. Melnik Jin Xue Orit Poulsen Michael J. Meehan Gregory Humphrey Lingjing Jiang Gail Ackermann Daniel McDonald Dan Zhou Rob Knight Pieter C. Dorrestein Gabriel G. Haddad Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome
description	ABSTRACT 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.
format	article
author	Anupriya Tripathi Alexey V. Melnik Jin Xue Orit Poulsen Michael J. Meehan Gregory Humphrey Lingjing Jiang Gail Ackermann Daniel McDonald Dan Zhou Rob Knight Pieter C. Dorrestein Gabriel G. Haddad
author_facet	Anupriya Tripathi Alexey V. Melnik Jin Xue Orit Poulsen Michael J. Meehan Gregory Humphrey Lingjing Jiang Gail Ackermann Daniel McDonald Dan Zhou Rob Knight Pieter C. Dorrestein Gabriel G. Haddad
author_sort	Anupriya Tripathi
title	Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome
title_short	Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome
title_full	Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome
title_fullStr	Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome
title_full_unstemmed	Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome
title_sort	intermittent hypoxia and hypercapnia, a hallmark of obstructive sleep apnea, alters the gut microbiome and metabolome
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c01326f5b4b0417ba6d9d3532c83605c
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Intermittent Hypoxia and Hypercapnia, a Hallmark of Obstructive Sleep Apnea, Alters the Gut Microbiome and Metabolome

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