Influence of Intermittent Hypoxia/Hypercapnia on Atherosclerosis, Gut Microbiome, and Metabolome.
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ABSTRACT:
SUBMITTER: Xue J
PROVIDER: S-EPMC8060652 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Obstructive sleep apnea (OSA), characterized by intermittent hypoxia and hypercapnia (IHC), affects the composition of the gut microbiome and metabolome. The gut microbiome has diurnal oscillations that play a crucial role in regulating circadian and overall metabolic homeostasis. Thus, we hypothesized that IHC adversely alters the gut luminal dynamics of key microbial families and metabolites. The objective of this study was to determine the diurnal dynamics of the fecal microbiome and metabolome of Apoe-/- mice after a week of IHC exposure. Individually housed, 10-week-old Apoe-/- mice on an atherogenic diet were split into two groups. One group was exposed to daily IHC conditions for 10 h (Zeitgeber time 2 [ZT2] to ZT12), while the other was maintained in room air. Six days after the initiation of the IHC conditions, fecal samples were collected every 4 h for 24 h (6 time points). We performed 16S rRNA gene amplicon sequencing and untargeted liquid chromatography-mass spectrometry (LC-MS) to assess changes in the microbiome and metabolome. IHC induced global changes in the cyclical dynamics of the gut microbiome and metabolome. Ruminococcaceae, Lachnospiraceae, S24-7, and Verrucomicrobiaceae had the greatest shifts in their diurnal oscillations. In the metabolome, bile acids, glycerolipids (phosphocholines and phosphoethanolamines), and acylcarnitines were greatly affected. Multi-omic analysis of these results demonstrated that Ruminococcaceae and tauro-β-muricholic acid (TβMCA) cooccur and are associated with IHC conditions and that Coriobacteriaceae and chenodeoxycholic acid (CDCA) cooccur and are associated with control conditions. IHC significantly change the diurnal dynamics of the fecal microbiome and metabolome, increasing members and metabolites that are proinflammatory and proatherogenic while decreasing protective ones. IMPORTANCE People with obstructive sleep apnea are at a higher risk of high blood pressure, type 2 diabetes, cardiac arrhythmias, stroke, and sudden cardiac death. We wanted to understand whether the gut microbiome changes induced by obstructive sleep apnea could potentially explain some of these medical problems. By collecting stool from a mouse model of this disease at multiple time points during the day, we studied how obstructive sleep apnea changed the day-night patterns of microbes and metabolites of the gut. Since the oscillations of the gut microbiome play a crucial role in regulating metabolism, changes in these oscillations can explain why these patients can develop so many metabolic problems. We found changes in microbial families and metabolites that regulate many metabolic pathways contributing to the increased risk for heart disease seen in patients with obstructive sleep apnea.
| S-EPMC8269208 | biostudies-literature
Project description:Studying perturbations in the gut ecosystem using animal models of disease continues to provide valuable insights into the role of the microbiome in various pathological conditions. However, understanding whether these changes are consistent across animal models of different genetic backgrounds, and hence potentially translatable to human populations, remains a major unmet challenge in the field. Nonetheless, in relatively limited cases have the same interventions been studied in two animal models in the same laboratory. Moreover, such studies typically examine a single data layer and time point. Here, we show the power of utilizing time series microbiome (16S rRNA amplicon profiling) and metabolome (untargeted liquid chromatography-tandem mass spectrometry [LC-MS/MS]) data to relate two different mouse models of atherosclerosis-ApoE-/- (n = 24) and Ldlr-/- (n = 16)-that are exposed to intermittent hypoxia and hypercapnia (IHH) longitudinally (for 10 and 6 weeks, respectively) to model chronic obstructive sleep apnea. Using random forest classifiers trained on each data layer, we show excellent accuracy in predicting IHH exposure within ApoE-/- and Ldlr-/- knockout models and in cross-applying predictive features found in one animal model to the other. The key microbes and metabolites that reproducibly predicted IHH exposure included bacterial species from the families Mogibacteriaceae, Clostridiaceae, bile acids, and fatty acids, providing a refined set of biomarkers associated with IHH. The results highlight that time series multiomics data can be used to relate different animal models of disease using supervised machine learning techniques and can provide a pathway toward identifying robust microbiome and metabolome features that underpin translation from animal models to human disease. IMPORTANCE Reproducibility of microbiome research is a major topic of contemporary interest. Although it is often possible to distinguish individuals with specific diseases within a study, the differences are often inconsistent across cohorts, often due to systematic variation in analytical conditions. Here we study the same intervention in two different mouse models of cardiovascular disease (atherosclerosis) by profiling the microbiome and metabolome in stool specimens over time. We demonstrate that shared microbial and metabolic changes are involved in both models with the intervention. We then introduce a pipeline for finding similar results in other studies. This work will help find common features identified across different model systems that are most likely to apply in humans.
| S-EPMC6495231 | biostudies-literature
Project description: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.
| S-EPMC5989129 | biostudies-literature
Project description:Chronic intermittent hypoxia (CIH) and chronic sleep fragmentation (CSF) are two cardinal pathological features of obstructive sleep apnea (OSA). Dietary obesity is a crucial risk intermediator for OSA and metabolic disorders. Gut microbiota affect hepatic and adipose tissue morphology under conditions of CIH or CSF through downstream metabolites. However, the exact relationship is unclear. Herein, chow and high-fat diet (HFD)-fed mice were subjected to CIH or CSF for 10 weeks each and compared to normoxia (NM) or normal sleep (NS) controls. 16S rRNA amplicon sequencing, untargeted liquid chromatography-tandem mass spectrometry, and histological assessment of liver and adipose tissues were used to investigate the correlations between the microbiome, metabolome, and lipid metabolism under CIH or CSF condition. Our results demonstrated that CIH and CSF regulate the abundance of intestinal microbes (such as Akkermansia mucinphila, Clostridium spp., Lactococcus spp., and Bifidobacterium spp.) and functional metabolites, such as tryptophan, free fatty acids, branched amino acids, and bile acids, which influence adipose tissue and hepatic lipid metabolism, and the level of lipid deposition in tissues and peripheral blood. In conclusion, CIH and CSF adversely affect fecal microbiota composition and function, and host metabolism; these findings provide new insight into the independent and synergistic effects of CIH, CSF, and HFD on lipid disorders.
| S-EPMC8846366 | biostudies-literature
Project description:Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established.The objective of the present study was to examine whether CIH may induce atherosclerosis in C57BL/6J mice.Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks.Nine of 10 mice simultaneously exposed to CIH and high-cholesterol diet developed atherosclerotic lesions in the aortic origin and descending aorta. In contrast, atherosclerosis was not observed in mice exposed to intermittent air and a high-cholesterol diet or in mice exposed to CIH and a regular diet. A high-cholesterol diet resulted in significant increases in serum total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol. Compared with mice exposed to intermittent air and a high-cholesterol diet, combined exposure to CIH and a high-cholesterol diet resulted in marked progression of dyslipidemia with further increases in serum total cholesterol and low-density lipoprotein cholesterol (124 +/- 4 vs. 106 +/- 6 mg/dl; p < 0.05), a twofold increase in serum lipid peroxidation, and up-regulation of an important hepatic enzyme of lipoprotein secretion, stearoyl-coenzyme A desaturase-1.CIH causes atherosclerosis in the presence of diet-induced dyslipidemia.
| S-EPMC2176090 | biostudies-other
Project description: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.
| S-EPMC8267877 | biostudies-literature
Project description:Comprehensive analyses of multi-omics data may provide insights into interactions between different biological layers concerning distinct clinical features. We integrated data on the gut microbiota, blood parameters and urine metabolites of treatment-naive individuals presenting a wide range of metabolic disease phenotypes to delineate clinically meaningful associations. Trans-omics correlation networks revealed that candidate gut microbial biomarkers and urine metabolite feature were covaried with distinct clinical phenotypes. Integration of the gut microbiome, the urine metabolome and the phenome revealed that variations in one of these three systems correlated with changes in the other two. In a specific note about clinical parameters of liver function, we identified Eubacteriumeligens, Faecalibacteriumprausnitzii and Ruminococcuslactaris to be associated with a healthy liver function, whereas Clostridium bolteae, Tyzzerellanexills, Ruminococcusgnavus, Blautiahansenii, and Atopobiumparvulum were associated with blood biomarkers for liver diseases. Variations in these microbiota features paralleled changes in specific urine metabolites. Network modeling yielded two core clusters including one large gut microbe-urine metabolite close-knit cluster and one triangular cluster composed of a gut microbe-blood-urine network, demonstrating close inter-system crosstalk especially between the gut microbiome and the urine metabolome. Distinct clinical phenotypes are manifested in both the gut microbiome and the urine metabolome, and inter-domain connectivity takes the form of high-dimensional networks. Such networks may further our understanding of complex biological systems, and may provide a basis for identifying biomarkers for diseases. Deciphering the complexity of human physiology and disease requires a holistic and trans-omics approach integrating multi-layer data sets, including the gut microbiome and profiles of biological fluids. By studying the gut microbiome on carotid atherosclerosis, we identified microbial features associated with clinical parameters, and we observed that groups of urine metabolites correlated with groups of clinical parameters. Combining the three data sets, we revealed correlations of entities across the three systems, suggesting that physiological changes are reflected in each of the omics. Our findings provided insights into the interactive network between the gut microbiome, blood clinical parameters and the urine metabolome concerning physiological variations, and showed the promise of trans-omics study for biomarker discovery.
| S-EPMC8529068 | biostudies-literature
Project description:Clinical trials have demonstrated the health benefits of intermittent fasting (IF). However, the potential mechanism of IF in alleviating dextran sulfate sodium (DSS)-induced colitis is not fully understood. The present study was mainly designed to explore the dynamic changes in the gut microbiota and metabolome after short-term (2 weeks) or long-term (20 weeks) IF and therefore clarify the potential mechanisms by which IF ameliorates DSS-induced colitis in a murine model. Thirty-two C57BL/6 male mice were equally divided into four groups and underwent IF intervention for 2 weeks (SIF group, n = 8), 20 weeks (LIF group, n = 8), or were allowed free access to food for 2 weeks (SAL group, n = 8) or 20 weeks (LAL group, n = 8). The thirty-two C57BL/6 male mice were accepted for the diet intervention of 2 weeks of IF or fed ad libitum. Colitis was induced by drinking 2% DSS for 7 days. Our findings showed that short-term IF prominently elevates the abundance of Bacteroides, Muibaculum and Akkermansia (p < 0.001, p < 0.001, p < 0.001, respectively), and decreased the abundance of Ruminiclostridium (p < 0.05). Long-term IF, however, decreased the abundance of Akkermansia and obviously increased the abundance of Lactobacillus (p < 0.05, p < 0.001, respectively). Metabolites mainly associated with nucleoside, carbohydrate, amino acid, bile acid, fatty acid, polyol, steroid and amine metabolism were identified in the faeces using untargeted GC/MS. In particular, inosine was extremely enriched after short-term IF and long-term IF (p < 0.01, p < 0.01, respectively); butyrate, 2-methyl butyric acid and valeric acid were significantly decreased after short-term IF (p < 0.001, p < 0.001, p < 0.01, respectively); and 2-methyl butyric acid was significantly increased after long-term IF (p < 0.001). The abundance of lithocholic acid (LCA), one of the secondary bile acids, increased significantly after short-term and long-term IF based on UPLC–MS/MS (p < 0.001, p < 0.5, respectively). Of note, IF markedly mitigated DSS-induced acute colitis symptoms and down-regulated pro-inflammatory cytokines IL-1α, IL-6, keratinocyte-derived chemokine (KC) and G-CSF levels in the serum (p < 0.01, p < 0.001, p < 0.05, p < 0.001, respectively). Furthermore, a correlation analysis indicated that the disease activity index (DAI) score and serum levels of IL-1α, IL-6, KC, and G-CSF were negatively correlated with the relative abundance of Akkermansia and the faecal metabolites LCA and inosine. This study confirmed that IF altered microbiota and reprogramed metabolism, which was a promising development in the attempt to prevent DSS-induced colitis. Moreover, our findings provide new insights regarding the correlations among the mucosal barrier dysfunction, metabolome, and microbiome.
| S-EPMC9788567 | biostudies-literature
Project description:BackgroundIntermittent hypoxia (IH), a typical character of obstructive sleep apnea (OSA), is related to atherogenesis. However, the role of IH on atherosclerosis (AS) progression and the mechanisms involved remains poorly understood.MethodsIn the present study, high-fat fed ApoE-/- mice were treated with recombinant shRNA-TLR4 lentivirus and exposed to IH. Atherosclerotic lesions on the en face aorta and cross-sections of aortic root were examined by Oil-Red O staining. The content of lipids and collagen of aortic root plaques were detected by Oil-Red O staining and Sirius red staining, respectively. The TLR4, NF-κB p65, α-SMA and MOMA-2 expression in aorta and IL-6 and TNF-α expression in the mice serum were also detected.ResultsCompared with the Sham group, the IH treated group further increased atherosclerotic plaque loads and plaque vulnerability in the aortic sinus. Along with increased TLR4 expression, enhanced NF-κB activation, inflammatory activity and aggravated dyslipidemia were observed in the IH treated group. TLR4 interference partly inhibited IH-mediated AS progression with decreased inflammation and improved cholesterol levels. Similarly, in endothelial cells, hypoxia/reoxygenation exposure has been shown to promote TLR4 expression and activation of proinflammatory TLR4/NF-κB signaling, while TLR4 interference inhibited these effects.ConclusionsWe found that the IH accelerated growth and vulnerability of atherosclerotic plaque, which probably acted by triggering the activation of proinflammatory TLR4/NF-κB signaling. These findings may suggest that IH is a risk factor for vulnerable plaque and provide a new insight into the treatment of OSA-induced AS progression.
| S-EPMC5907703 | biostudies-literature
Project description:BackgroundGut microbiota (GM) contribute to obesity and insulin resistance (IR). Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), promotes IR and alters GM. Since circulating exosomes are implicated in IR, we examined the effects of IH and physical activity (PA) in mice on GM, colonic epithelium permeability, systemic IR, and plasma exosome cargo, and exosome effects on visceral white adipose tissues (vWAT) IR.MethodsC57BL/6 mice were exposed to IH or room air (RA) for 6 weeks with and without PA (n = 12/group), and GM and systemic IR changes were assessed, as well as the effects of plasma exosomes on naïve adipocyte insulin sensitivity. Fecal microbiota transfers (FMT) were performed in naïve mice (n = 5/group), followed by fecal 16S rRNA sequencing, and systemic IR and exosome-induced effects on adipocyte insulin sensitivity were evaluated.FindingsPrincipal coordinate analysis (PCoA) ordinates revealed B-diversity among IH and FMT recipients that accounted for 64% principal component 1 (PC1) and 12.5% (PC2) of total variance. Dominant microbiota families and genera in IH-exposed and FMT-treated were preserved, and IH-exposed GM and IH-FMT induced increased gut permeability. Plasma exosomes from IH-exposed and IH-FMT mice decreased pAKT/AKT responses to exogenous insulin in adipocytes vs. IH+PA or RA FMT-treated mice (p = 0.001).InterpretationIH exposures mimicking OSA induce changes in GM, increase gut permeability, and alter plasma exosome cargo, the latter inducing adipocyte dysfunction (increased IR). Furthermore, these alterations improved with PA. Thus, IH leads to perturbations of a singular GM-circulating exosome pathway that disrupts adipocyte homeostasis resulting in metabolic dysfunction, as reflected by IR.FundingThis study was supported by grants from the National Institutes of Health grants HL130984 and HL140548 and University of Missouri Tier 2 grant. The study has not received any funding or grants from pharmaceutical or other industrial corporations.
| S-EPMC7910674 | biostudies-literature