Disturbances of the Gut Microbiota, Sleep Architecture, and mTOR Signaling Pathway in Patients with Severe Obstructive Sleep Apnea-Associated Hypertension
Chih‐Yuan Ko, Huan‐Zhang Su, Li Zhang, Yiming Zeng
Abstract
Intermittent hypoxia and sleep fragmentation are pathophysiological processes involved in obstructive sleep apnea (OSA) which affect gut microbiota, sleep architecture, and mTOR signaling pathway. However, the involvement of these elements in the pathogenesis mechanism of OSA-associated hypertension remains unclear. Therefore, this study investigated whether the OSA-associated hypertension mechanism is regulated by the gut microbiota and mTOR signaling pathway. Patients were diagnosed by polysomnography; their fecal samples were obtained and analyzed for their microbiome composition by 16S ribosomal RNA pyrosequencing and bioinformatics analysis. Transcript genes on fasting peripheral blood mononuclear cells (PBMCs) were examined using Illumina RNA-sequencing analysis. Totally, we enrolled 60 patients with severe OSA [without hypertension (n = 27) and with hypertension (n = 33)] and 12 controls (neither OSA nor hypertension). Results revealed that severe-OSA patients with hypertension had an altered gut microbiome, decreased short-chain fatty acid-producing bacteria <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mfenced open="(" close=")" separators="|"> <a:mrow> <a:mi>P</a:mi> <a:mo><</a:mo> <a:mn>0.05</a:mn> </a:mrow> </a:mfenced> </a:math> , and reduced arginine and proline metabolism pathways <f:math xmlns:f="http://www.w3.org/1998/Math/MathML" id="M2"> <f:mfenced open="(" close=")" separators="|"> <f:mrow> <f:mi>P</f:mi> <f:mo>=</f:mo> <f:mn>0.001</f:mn> </f:mrow> </f:mfenced> </f:math> , compared with controls; also, they had increased stage N1 sleep and reduced stages N2 and N3 sleep accompanied by repeated arousals <k:math xmlns:k="http://www.w3.org/1998/Math/MathML" id="M3"> <k:mfenced open="(" close=")" separators="|"> <k:mrow> <k:mi>P</k:mi> <k:mo><</k:mo> <k:mn>0.05</k:mn> </k:mrow> </k:mfenced> </k:math> . Analysis of PBMCs using the Kyoto Encyclopedia of Genes and Genomes database showed that the mTOR signaling pathway <p:math xmlns:p="http://www.w3.org/1998/Math/MathML" id="M4"> <p:mfenced open="(" close=")" separators="|"> <p:mrow> <p:mi>P</p:mi> <p:mo>=</p:mo> <p:mn>0.006</p:mn> </p:mrow> </p:mfenced> </p:math> was the most important differential gene-enriched pathway in severe-OSA patients with hypertension. Our findings extend prior work and suggest a possibility that the regulation of the mTOR signaling pathway is involved in developing OSA-associated hypertension through its interaction with the disturbance of the gut microbiome and sleep architecture.