Microbiota Modulates Cardiac Transcriptional Responses to Intermittent Hypoxia and Hypercapnia.

Dan Zhou,Lars Eckmann,Gabriel G Haddad,Yukiko Miyamoto,Jin Xue,Orit Poulsen

doi:10.3389/fphys.2021.680275

Abstract

The microbiota plays a critical role in regulating organismal health and response to environmental stresses. Intermittent hypoxia and hypercapnia, a condition that represents the main hallmark of obstructive sleep apnea in humans, is known to induce significant alterations in the gut microbiome and metabolism, and promotes the progression of atherosclerosis in mouse models. To further understand the role of the microbiome in the cardiovascular response to intermittent hypoxia and hypercapnia, we developed a new rodent cage system that allows exposure of mice to controlled levels of O2 and CO2 under gnotobiotic conditions. Using this experimental setup, we determined the impact of the microbiome on the transcriptional response to intermittent hypoxia and hypercapnia in the left ventricle of the mouse heart. We identified significant changes in gene expression in both conventionally reared and germ-free mice. Following intermittent hypoxia and hypercapnia exposure, we detected 192 significant changes in conventionally reared mice (96 upregulated and 96 downregulated) and 161 significant changes (70 upregulated and 91 downregulated) in germ-free mice. Only 19 of these differentially expressed transcripts (∼10%) were common to conventionally reared and germ-free mice. Such distinct transcriptional responses imply that the host microbiota plays an important role in regulating the host transcriptional response to intermittent hypoxia and hypercapnia in the mouse heart.

Highlights

Obstructive sleep apnea (OSA) is the most common type of sleep disorder in humans, and OSA is very prevalent in adults and children
GF mice could be kept in the system for extended periods (>2 weeks) without compromising their GF state, demonstrating that the newly developed system was well suited to conduct short- and long-term experiments of constant or intermittent hypoxia with or without hypercapnia under gnotobiotic conditions
Since (1) Myc-mediated apoptosis plays a critical role in response to stress in the myocardium (Hou et al, 2016; Veeraveedu et al, 2017; Guan et al, 2019), (2) NFAT plays a major role in cardiac hypertrophy [for selected reviews see Clerk et al (2007), Rohini et al (2010), Nakayama et al (2013)], and (3) previous studies shown that gut microbiome regulates the activity of Myc in mouse liver (Kolodziejczyk et al, 2020) and NFAT in colorectal cancer in humans (Peuker et al, 2016), our current findings suggest that alterations of Myc and NFAT signaling in GF mice may modify cardiac activity and stress response

Summary

Introduction

Obstructive sleep apnea (OSA) is the most common type of sleep disorder in humans, and OSA is very prevalent in adults and children It is characterized by repeated episodes of complete or partial obstructions of the upper airways during sleep, which is associated with a reduction in blood oxygen saturation and an increase in blood CO2. It has been demonstrated by experimental and clinical studies that OSA may lead to a number of health consequences including cardiovascular diseases ranging from cardiometabolic disorders and arrhythmogenesis to heart failure (Al Lawati et al, 2009; Baguet et al, 2012; Levy et al, 2013; Drager et al, 2015; Lyons and Bradley, 2015; Hoyos et al, 2017; May et al, 2017). Recent studies revealed a potential contribution of gut microbes to certain human cardiometabolic diseases (Vinje et al, 2014) and heart failure (Sandek et al, 2007; Nagatomo and Tang, 2015; Nemet et al, 2020)

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Conclusion