Abstract P473: Obstructive Sleep Apnea Results In Microbial Bile Acid Biotransformations To Promote Atherosclerosis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Amulya Lingaraju ◽  
Stephany Flores Ramos ◽  
Emily Gentry ◽  
Orit Poulsen ◽  
Pieter C Dorrestein ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Bile Acid ◽  
Sleep Apnea ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Atherosclerotic Lesion ◽  
Farnesoid X Receptor ◽  
Lesion Formation ◽  
Aortic Lesion ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is an independent exacerbator of cardiovascular disease (CVD). However, it is unclear how OSA or it’s characteristic components, intermittent hypoxia and hypercapnia (IHC), increase CVD risk. Our previous work has shown that IHC reproducibly changes the gut microbiome dynamics in murine models of atherosclerosis and that these changes could affect host cardiovascular physiology through bile acids and phosphocholines. In our initial targeted metabolomics approach, changes in particular bile acids, such as taurocholic acid, taurodeoxycholic acid, and muricholic acid, were associated with and were predictive of IHC exposure in atherosclerotic Ldlr-/- mice. In a more recent study, we identified the formation of novel, microbially-synthesized conjugated bile acids by the gut microbiome that are more potent farnesoid X receptor agonists than other previously described bile acids, and thus, potentially can affect atherosclerosis formation. To determine whether these novel bile acids are associated with IHC-induced atherosclerosis, we characterized luminal bile acid changes in Ldlr-/- mice in an OSA model. We hypothesize that IHC alters the amount of microbially-synthesized novel bile acids and that these bile acids are associated with IHC-induced atherosclerosis. To test this hypothesis, we subjected atherogenic diet-fed Ldlr-/- mice to either room-air (control) or IHC conditions (n=10/condition) and assessed atherosclerotic lesion formation after 12 weeks post-diet. Mice under IHC conditions had significantly higher aortic lesion formation compared to controls. Assessment of fecal bile acid metabolites indicated changes in novel bile acid levels under IHC conditions. Moreover, correlational analysis showed that these novel bile acid changes were positively correlated with atherosclerotic lesion amounts, mainly driven by IHC conditions. Our results demonstrate that bile acid changes through microbial biotransformations occur under IHC conditions and could be the mechanistic link between OSA-induced microbiome changes and atherosclerosis.

130 A MURINE MODEL OF OBSTRUCTIVE SLEEP APNEA REVEALS EARLY MARKERS OF DYSMETABOLISM IN THE GUT MICROBIOME AND METABOLOME

2020 ◽  
Vol 158 (6) ◽  
pp. S-25-S-26
Author(s):  
Celeste Allaband ◽  
Amulya Lingaraju ◽  
Anupriya Tripathi ◽  
Baylee J. Russell ◽  
Orit Poulsen ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Murine Model ◽  
Gut Microbiome ◽  
Obstructive Sleep ◽  
Early Markers

scholarly journals The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

2021 ◽  
Vol 14 ◽  
pp. 175628482110177
Author(s):  
Benjamin H. Mullish ◽  
Jessica R. Allegretti
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Acid Metabolism ◽  
Disease Process ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Clostridioides Difficile ◽  
Gut Barrier Function ◽  
Clostridioides Difficile Infection

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites – in particular, bile acid metabolism – being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) – with a resulting alteration of the gut bile acid milieu – contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other ‘next generation’ FMT products) designed to treat CDI may be critical to their success.

scholarly journals Obstructive sleep apnea and hypertension: the role of gut microbiome

2020 ◽  
Vol 66 (7) ◽  
pp. 415-419
Author(s):  
Pavel Šiarnik ◽  
Katarína Klobučníková ◽  
Imrich Mucska ◽  
Alžbeta Hlucháňová ◽  
Oto Hanus ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Gut Microbiome ◽  
Obstructive Sleep

scholarly journals Disturbances of the Gut Microbiota, Sleep Architecture, and mTOR Signaling Pathway in Patients with Severe Obstructive Sleep Apnea-Associated Hypertension

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Chih-Yuan Ko ◽  
Huan-Zhang Su ◽  
Li Zhang ◽  
Yi-Ming Zeng
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Gut Microbiota ◽  
Signaling Pathway ◽  
Gut Microbiome ◽  
Mtor Signaling ◽  
Sleep Architecture ◽  
Sequencing Analysis ◽  
Mtor Signaling Pathway ◽  
Obstructive Sleep

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 P < 0.05 , and reduced arginine and proline metabolism pathways P = 0.001 , compared with controls; also, they had increased stage N1 sleep and reduced stages N2 and N3 sleep accompanied by repeated arousals P < 0.05 . Analysis of PBMCs using the Kyoto Encyclopedia of Genes and Genomes database showed that the mTOR signaling pathway P = 0.006 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.

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

mSystems ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Anupriya Tripathi ◽  
Alexey V. Melnik ◽  
Jin Xue ◽  
Orit Poulsen ◽  
Michael J. Meehan ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Gut Microbiome ◽  
Intermittent Hypoxia ◽  
Joint Analysis ◽  
Gut Microbes ◽  
Causal Pathways ◽  
Obstructive Sleep ◽  
Cardiometabolic Disorders ◽  
The Impact

ABSTRACTObstructive 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 O2and CO2can 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 usingLdlr−/−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 inClostridia) 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.IMPORTANCEIntestinal 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.

scholarly journals Role of the Gut Microbiome in Obstructive Sleep Apnea–Induced Hypertension

Hypertension ◽  
2016 ◽  
Vol 67 (2) ◽  
pp. 469-474 ◽  
Author(s):  
David J. Durgan ◽  
Bhanu P. Ganesh ◽  
Julia L. Cope ◽  
Nadim J. Ajami ◽  
Sharon C. Phillips ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Gut Microbiome ◽  
Obstructive Sleep ◽  
Induced Hypertension
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