scholarly journals Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

2018 ◽  
Vol 314 (5) ◽  
pp. E468-E477 ◽  
Author(s):  
Micah L. Battson ◽  
Dustin M. Lee ◽  
Dillon K. Jarrell ◽  
Shuofei Hou ◽  
Kayl E. Ecton ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Gut Microbiota ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Nuclear Factor Κb ◽  
Western Diet ◽  
Standard Diet ◽  
Vascular Abnormalities ◽  
Gut Dysbiosis

Vascular dysfunction represents a critical preclinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesity-related vascular dysfunction. Male C57BL/6J mice were fed either a standard diet (SD) ( n = 12) or Western diet (WD) ( n = 24) for 5 mo, after which time WD mice were randomized to receive either unsupplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD + Abx) ( n = 12/group) for 2 mo. Seven months of WD caused gut dysbiosis, increased arterial stiffness (SD 412.0 ± 6.0 vs. WD 458.3 ± 9.0 cm/s, P < 0.05) and endothelial dysfunction (28% decrease in max dilation, P < 0.05), and reduced l-NAME-inhibited dilation. Vascular dysfunction was accompanied by significant increases in circulating LPS-binding protein (LBP) (SD 5.26 ± 0.23 vs. WD 11 ± 0.86 µg/ml, P < 0.05) and interleukin-6 (IL-6) (SD 3.27 ± 0.25 vs. WD 7.09 ± 1.07 pg/ml, P < 0.05); aortic expression of phosphorylated nuclear factor-κB (p-NF-κB) ( P < 0.05); and perivascular adipose expression of NADPH oxidase subunit p67phox ( P < 0.05). Impairments in vascular function correlated with reductions in Bifidobacterium spp. Antibiotic treatment successfully abrogated the gut microbiota and reversed WD-induced arterial stiffness and endothelial dysfunction. These improvements were accompanied by significant reductions in LBP, IL-6, p-NF-κB, and advanced glycation end products (AGEs), and were independent from changes in body weight and glucose tolerance. These results indicate that gut dysbiosis contributes to the development of WD-induced vascular dysfunction, and identify the gut microbiota as a novel therapeutic target for obesity-related vascular abnormalities.

scholarly journals Cardiometabolic Effects of a Gut Microbial Metabolite of Tryptophan in Western Diet-fed Mice (P21-025-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Dustin Lee ◽  
Christopher Gentile ◽  
Tiffany Weir ◽  
Scott Wrigley ◽  
S Raj Trikha ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Glucose Tolerance ◽  
Gut Microbiota ◽  
Intestinal Permeability ◽  
Dietary Intervention ◽  
Vascular Dysfunction ◽  
Aortic Pulse Wave Velocity ◽  
Western Diet ◽  
Standard Diet ◽  
Funding Sources

Abstract Objectives Our lab has recently established that the gut microbiota regulates obesity-related vascular dysfunction. However, the specific mechanisms by which the gut microbiota regulates host physiology remain obscure. Indoles are products of bacterial tryptophan metabolism and have been shown to exert various physiological effects on the host. In the current study, we examine the effects of indole-3-propionic acid (IPA) on cardiometabolic outcomes in western diet-fed mice. Methods Male C57BL/6 mice were fed either and standard diet (SD) or western diet (WD) for 5-months (mo). Two additional groups were fed the same diets and supplemented with IPA (SD + IPA and WD + IPA) in autoclaved drinking water (0.1 mg/ml) during the dietary intervention. After 5mo, arterial stiffness was assessed by aortic pulse wave velocity (aPWV). Intestinal permeability was measured with FITC-dextran. Glucose tolerance was assessed after a 6 hour fast followed by intraperitoneal injection of 2 g/kg glucose solution. Results Both WD-fed groups displayed significantly higher body weight than SD and SD + IPA (P < 0.05) with no effect of IPA supplementation. aPWV was significantly higher in WD and WD + IPA compared to SD (485.7 ± 6.7 & 492.8 ± 8.6 vs 436.9 ± 7.0 cm/s, P < 0.05), whereas the SD + IPA was not significantly different than either WD-fed groups (468.1 ± 6.6, P > 0.05). Supplementation with IPA in the SD + IPA group significantly increased glucose AUC compared to SD mice (1763.3 ± 92.0 vs 1397.6 ± 64.0, P < 0.05) and no significant differences were observed with either WD or WD + IPA groups (1623.5 ± 77.3 & 1658.4 ± 88.4, P > 0.05). No significant differences were observed between groups with regard to intestinal permeability. Conclusions In the current study, supplementation with IPA in WD-fed mice did not affect arterial stiffness, glucose tolerance, or intestinal permeability. Future analyses will determine other cardiometabolic effects and characterize the gut microbiota. Funding Sources Colorado Agricultural Experimental Station Research Grant #COL00766.

scholarly journals The Gut Microbiota Is Associated with Vascular Function and Blood Pressure Phenotypes in Overweight and Obese Middle-Aged/Older Adults (P21-024-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sarah Johnson ◽  
Nicole Litwin ◽  
Hannah Van Ark ◽  
Shannon Hartley ◽  
Emily Fischer ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Stiffness ◽  
Gut Microbiota ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Reactive Hyperemia ◽  
Bifidobacterium Longum ◽  
Middle Aged ◽  
Principal Coordinates ◽  
The Relationship

Abstract Objectives The gut microbiota is emerging as an important regulator of cardiovascular health. Indeed, gut dysbiosis is increasingly being linked to the development of cardiovascular disease (CVD). Aging and obesity are associated with the development of CVD largely due to the development of vascular dysfunction, namely endothelial dysfunction and arterial stiffness. The objective of this study was to examine the relationship between the gut microbiota, blood pressure, and vascular function in aging overweight and obese individuals. Methods This cross-sectional study included fifteen overweight and obese (mean body mass index, BMI: 29.5; range: 25.8–37.0) middle-aged/older men and postmenopausal women (mean age: 53; range: 42–64 years). Blood pressure, arterial stiffness (augmentation index, AIx, and aortic pulse wave velocity, aPWV), and endothelial function (reactive hyperemia index, RHI) were assessed. Stool samples were collected for gut microbiota analysis using 16S ribosomal RNA sequencing. Principal coordinates analysis and Pearson's correlations were performed to evaluate the relationship between the gut microbiota and measures of vascular function and blood pressure. Results Global gut microbiota phenotypes clustered most strongly by aPWV (groups separated by median value) as visualized by Non-Metric Dimensional Scaling plot of Bray-Curtis Distances (stress = 0.09; P = 0.07). Several bacterial taxa correlated with vascular parameters. For example, Bifidobacterium longum (r = 0.80, P < 0.001) and Akkermansia muciniphila (r = 0.56, P = 0.047) were positively correlated with RHI. Bifdobacterium bifidum (r = −0.61, P = 0.02) and Oxalobacter formigenes (r = −0.62, P = 0.02) were negatively correlated with systolic blood pressure. Interestingly, there was no significant clustering by BMI groupings (overweight vs. obese) or correlations between BMI and specific taxa. Conclusions These preliminary data suggest that the gut microbiota is linked to vascular dysfunction and increased blood pressure in aging overweight and obese individuals independent of BMI. Further data collection and analysis are currently underway to explore these relationships in a larger human cohort, and to explore underlying mechanisms through transferring of vascular phenotypes in humans to germ-free mice through microbiota transplantation. Funding Sources NIFA, USDA.

scholarly journals Effects of L-Citrulline Supplementation and Aerobic Training on Vascular Function in Individuals with Obesity across the Lifespan

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2991
Author(s):  
Anaisa Genoveva Flores-Ramírez ◽  
Verónica Ivette Tovar-Villegas ◽  
Arun Maharaj ◽  
Ma Eugenia Garay-Sevilla ◽  
Arturo Figueroa
Keyword(s):  
Risk Factors ◽  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Vascular Function ◽  
Cardiometabolic Risk ◽  
Aerobic Training ◽  
Cardiometabolic Risk Factors ◽  
No Production ◽  
Vascular Abnormalities ◽  
Training Interventions

Children with obesity are at higher risk for developing cardiometabolic diseases that once were considered health conditions of adults. Obesity is commonly associated with cardiometabolic risk factors such as dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension that contribute to the development of endothelial dysfunction. Endothelial dysfunction, characterized by reduced nitric oxide (NO) production, precedes vascular abnormalities including atherosclerosis and arterial stiffness. Thus, early detection and treatment of cardiometabolic risk factors are necessary to prevent deleterious vascular consequences of obesity at an early age. Non-pharmacological interventions including L-Citrulline (L-Cit) supplementation and aerobic training stimulate endothelial NO mediated vasodilation, leading to improvements in organ perfusion, blood pressure, arterial stiffness, atherosclerosis and metabolic health (glucose control and lipid profile). Few studies suggest that the combination of L-Cit supplementation and exercise training can be an effective strategy to counteract the adverse effects of obesity on vascular function in older adults. Therefore, this review examined the efficacy of L-Cit supplementation and aerobic training interventions on vascular and metabolic parameters in obese individuals.

scholarly journals Gut microbiota from coronary artery disease patients contributes to vascular dysfunction in mice by regulating bile acid metabolism and immune activation

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Honghong Liu ◽  
Ran Tian ◽  
Hui Wang ◽  
Siqin Feng ◽  
Hanyu Li ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Arterial Stiffness ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Bile Acid Metabolism ◽  
Clostridium Symbiosum ◽  
Artery Disease

Abstract Background The gut microbiota was shown to play a crucial role in the development of vascular dysfunction, and the bacterial composition differed between healthy controls and coronary artery disease patients. The goal of this study was to investigate how the gut microbiota affects host metabolic homeostasis at the organism scale. Methods We colonized germ-free C57BL/6 J mice with faeces from healthy control donors (Con) and coronary artery disease (CAD) patients and fed both groups a high fat diet for 12 weeks. We monitored cholesterol and vascular function in the transplanted mice. We analysed bile acids profiles and gut microbiota composition. Transcriptome sequencing and flow cytometry were performed to evaluate inflammatory and immune response. Results CAD mice showed increased reactive oxygen species generation and intensive arterial stiffness. Microbiota profiles in recipient mice clustered according to the microbiota structure of the human donors. Clostridium symbiosum and Eggerthella colonization from CAD patients modulated the secondary bile acids pool, leading to an increase in lithocholic acid and keto-derivatives. Subsequently, bile acids imbalance in the CAD mice inhibited hepatic bile acids synthesis and resulted in elevated circulatory cholesterol. Moreover, the faecal microbiota from the CAD patients caused a significant induction of abnormal immune responses at both the transcriptome level and through the enhanced secretion of cytokines. In addition, microbes belonging to CAD promoted intestinal inflammation by contributing to lamina propria Th17/Treg imbalance and worsened gut barrier permeability. Conclusions In summary, our findings elucidated that the gut microbiota impacts cholesterol homeostasis by modulating bile acids. In addition, the CAD-associated bacterial community was shown to function as an important regulator of systemic inflammation and to influence arterial stiffness.

scholarly journals Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Satomi Kagota ◽  
Kana Maruyama ◽  
John J. McGuire
Keyword(s):  
Systematic Review ◽  
Metabolic Syndrome ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Cell Surface Receptor ◽  
Metabolic Dysfunction ◽  
The Face ◽  
Surface Receptor ◽  
Treatment Of Obesity

Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds. Interest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial dysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity, diabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of the published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic syndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models differed amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial dysfunction. The remaining studies focused on nonvascular functions and provided evidence supporting the concept that PAR2 activation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists inhibited adipose gain and metabolic dysfunction in rats. We conclude that PAR2 antagonists for treatment of obesity indeed show early promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce vascular dysfunction in diabetes, warrant additional study.

scholarly journals AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice fed a high-fat diet

2021 ◽  
Author(s):  
Raquel González-Blázquez ◽  
Martín Alcalá ◽  
José Miguel Cárdenas ◽  
Marta Viana ◽  
Ulrike Muscha Steckelings ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Abdominal Aorta ◽  
High Fat Diet ◽  
Vascular Function ◽  
Collagen Deposition ◽  
High Fat ◽  
Ecm Remodeling ◽  
Diet Induced Obesity ◽  
Compound 21

The aim of this study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). &#160;5-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1mg/kg/day, in the drinking water), generating 4 groups: Chow C, Chow C21, HF C, HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition, activity of metalloproteinases (MMP) 2 and 9 and TGF-b1 concentration were analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, paralleled by an augmented β-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-b1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice.&lt;/p&gt; &#160;In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.

Abstract 211: The DPP-4 Inhibitor Linagliptan Reverses Endothelial Dysfunction of Mesenteric Arteries From Rats Fed a Western Diet

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Salheen M Salheen ◽  
Jason C Nguyen ◽  
Trisha A Jenkins ◽  
Owen L Woodman
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Western Diet ◽  
Mesenteric Arteries ◽  
Standard Diet ◽  
High Fat ◽  
Total Fat ◽  
Endothelium Dependent Relaxation ◽  
Superoxide Release

A high-fat ‘western’ diet (WD), a risk factor for the development of type 2 diabetes, may cause endothelial dysfunction one of the earliest events in atherogenesis. The dipeptidyl peptidase-4 (DPP-4) inhibitors are used to lower hyperglycemia in type 2 diabetes which is also associated with endothelial dysfunction. We tested whether consumption of a WD affected endothelium-dependent relaxation (EDR) of rat mesenteric arteries (MA) and whether the DPP-4 inhibitor linagliptin (1μM) improves EDR. Wistar Hooded rats were fed a standard diet (SD, 7% total fat) or WD (21% total fat) for 10 weeks. Consumption of the WD significantly increased superoxide release from MA assayed by lucigenin chemiluminescence (WD 1210±180 counts/mg versus SD 543±156 counts/mg, n=7-8, p<0.05) and linagliptin significantly reduced the vascular superoxide release (WD+linagliptin 432±102 counts/mg, p<0.05). Acetylcholine (ACh)-induced endothelium-dependent relaxation of MA was assessed using wire myography. WD significantly reduced the sensitivity to ACh (pEC50, SD 7.72±0.08, WD, 7.32±0.05 n=8, p<0.05) and treatment with linagliptin improved endothelial function (ACh pEC50 WD+linagliptin, 7.74±0.12, n=8, p<0.05). The contribution of EDHF to ACh-induced relaxation was determined in the presence of L-NNA and ODQ to block NOS and guanylate cyclase. EDHF-mediated relaxation was improved by linagliptin (pEC50, WD 6.24±0.06, WD+linagliptin 6.95±0.12, n=4-5, p<0.05). Linagliptin also significantly improved the contribution of NO (determined in the presence of TRAM-34 + apamin to block IKCa and SKCa) to relaxation (pEC50, WD 6.50±0.13, WD+linagliptin 7.30±0.10 n=4-6, p<0.05). Linagliptin significantly reduced vascular superoxide levels and improved the contribution of both NO and EDHF to preserve endothelium-dependent relaxation in rats fed a high fat diet. DPP-4 inhibition may have effects in addition to the lowering of plasma glucose to improve vascular function in diabetes.

scholarly journals Context-dependent effects of SOCS3 in angiotensin II-induced vascular dysfunction and hypertension in mice: mechanisms and role of bone marrow-derived cells

2016 ◽  
Vol 311 (1) ◽  
pp. H146-H156 ◽  
Author(s):  
Ying Li ◽  
Dale A. Kinzenbaw ◽  
Mary L. Modrick ◽  
Lecia L. Pewe ◽  
Frank M. Faraci
Keyword(s):  
Bone Marrow ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Carotid Artery Disease ◽  
Vascular Dysfunction ◽  
Cytokine Signaling ◽  
Ang Ii ◽  
Direct Effects ◽  
Bone Marrow Derived Cells

Carotid artery disease is a major contributor to stroke and cognitive deficits. Angiotensin II (Ang II) promotes vascular dysfunction and disease through mechanisms that include the IL-6/STAT3 pathway. Here, we investigated the importance of suppressor of cytokine signaling 3 (SOCS3) in models of Ang II-induced vascular dysfunction. We examined direct effects of Ang II on carotid arteries from SOCS3-deficient (SOCS3+/−) mice and wild-type (WT) littermates using organ culture and then tested endothelial function with acetylcholine (ACh). A low concentration of Ang II (1 nmol/l) did not affect ACh-induced vasodilation in WT but reduced that of SOCS3+/−mice by ∼50% ( P < 0.05). In relation to mechanisms, effects of Ang II in SOCS3+/−mice were prevented by inhibitors of STAT3, IL-6, NF-κB, or superoxide. Systemic Ang II (1.4 mg/kg per day for 14 days) also reduced vasodilation to ACh in WT. Surprisingly, SOCS3 deficiency prevented most of the endothelial dysfunction. To examine potential underlying mechanisms, we performed bone marrow transplantation. WT mice reconstituted with SOCS3+/−bone marrow were protected from Ang II-induced endothelial dysfunction, whereas reconstitution of SOCS3+/−mice with WT bone marrow exacerbated Ang II-induced effects. The SOCS3 genotype of bone marrow-derived cells did not influence direct effects of Ang II on vascular function. These data provide new mechanistic insight into the influence of SOCS3 on the vasculature, including divergent effects depending on the source of Ang II. Bone marrow-derived cells deficient in SOCS3 protect against systemic Ang II-induced vascular dysfunction.

scholarly journals Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction

Gut ◽  
2017 ◽  
Vol 67 (2) ◽  
pp. 271-283 ◽  
Author(s):  
Emilie Catry ◽  
Laure B Bindels ◽  
Anne Tailleux ◽  
Sophie Lestavel ◽  
Audrey M Neyrinck ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Gut Microbiota ◽  
Vascular Function ◽  
Carotid Arteries ◽  
Rrna Gene ◽  
Gut Peptides ◽  
Novel Approach

ObjectiveTo investigate the beneficial role of prebiotics on endothelial dysfunction, an early key marker of cardiovascular diseases, in an original mouse model linking steatosis and endothelial dysfunction.DesignWe examined the contribution of the gut microbiota to vascular dysfunction observed in apolipoprotein E knockout (Apoe−/−) mice fed an n-3 polyunsaturated fatty acid (PUFA)-depleted diet for 12 weeks with or without inulin-type fructans (ITFs) supplementation for the last 15 days. Mesenteric and carotid arteries were isolated to evaluate endothelium-dependent relaxation ex vivo. Caecal microbiota composition (Illumina Sequencing of the 16S rRNA gene) and key pathways/mediators involved in the control of vascular function, including bile acid (BA) profiling, gut and liver key gene expression, nitric oxide and gut hormones production were also assessed.ResultsITF supplementation totally reverses endothelial dysfunction in mesenteric and carotid arteries of n-3 PUFA-depleted Apoe−/− mice via activation of the nitric oxide (NO) synthase/NO pathway. Gut microbiota changes induced by prebiotic treatment consist in increased NO-producing bacteria, replenishment of abundance in Akkermansia and decreased abundance in bacterial taxa involved in secondary BA synthesis. Changes in gut and liver gene expression also occur upon ITFs suggesting increased glucagon-like peptide 1 production and BA turnover as drivers of endothelium function preservation.ConclusionsWe demonstrate for the first time that ITF improve endothelial dysfunction, implicating a short-term adaptation of both gut microbiota and key gut peptides. If confirmed in humans, prebiotics could be proposed as a novel approach in the prevention of metabolic disorders-related cardiovascular diseases.

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