GUT MICROBIOTA AND BILE ACIDS METABOLISM AT THE CROSSROAD BETWEEN CHOLESTEROL HOMEOSTASIS AND CHRONIC INFLAMMATION IN ENDOTHELIAL DYSFUNCTION AND ARTERIAL STIFFNESS

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.

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Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00187.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. E468-E477 ◽

Cited By ~ 27

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.

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Chlorothalonil induces metabolic syndrome in mice by regulating host gut microbiota and bile acids metabolism via FXR pathways

10.21203/rs.3.rs-1000136/v1 ◽

2021 ◽

Author(s):

Zhiyuan Meng ◽

Sen Yan ◽

Wei Sun ◽

Jin Yan ◽

Miaomiao Teng ◽

...

Keyword(s):

Metabolic Syndrome ◽

Gut Microbiota ◽

Bile Acids ◽

Low Dose ◽

Daily Intake ◽

Dependent Manner ◽

Glycolipid Metabolism ◽

Pesticides Exposure ◽

Bile Acids Metabolism

Abstract Background：The most commonly used organochlorine pesticide, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet.Results: This study found that the low-dose CHI based on acceptable daily intake (ADI) level could induce metabolic syndrome (MetS) in mice, including obesity, hepatic steatosis, dyslipidemia, and insulin resistance. In addition, exposure to low-dose CHI could induce an imbalance in the gut microbiota of mice, resulting in a significant increase in the ratio of Firmicutes to Bacteroidetes. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the low-dose CHI could induce MetS in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, the low-dose CHI could disturb the serum metabolism of bile acids (BAs) in mice, causing the inhibition of the signal response of BAs receptor farnesol X receptor (FXR) and leading to glycolipid metabolism disorders in liver tissue and epididymal white adipose tissue (epiWAT) of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the low-dose CHI-induced MetS in mice.Conclusions: In conclusion, the low-dose CHI was found to induce MetS in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of MetS, demonstrating the key role of gut microbiota in the toxic effects of pesticides.

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

Journal of Translational Medicine ◽

10.1186/s12967-020-02539-x ◽

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.

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Geniposide Improves Cholesterol Homeostasis by Regulating FXR-Mediated Liver-Gut Crosstalk of Bile Acids

SSRN Electronic Journal ◽

10.2139/ssrn.3403347 ◽

2019 ◽

Author(s):

Jinxin Liu ◽

Yan Li ◽

Haiou Pan ◽

Mingcong Fan ◽

Lamei Xue ◽

...

Keyword(s):

Bile Acids ◽

Cholesterol Homeostasis

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Baitouweng Tang ameliorates DSS-induced ulcerative colitis through the regulation of the gut microbiota and bile acids via pathways involving FXR and TGR5

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111320 ◽

2021 ◽

Vol 137 ◽

pp. 111320

Author(s):

Yong-li Hua ◽

Ya-qian Jia ◽

Xiao-song Zhang ◽

Zi-wen Yuan ◽

Peng Ji ◽

...

Keyword(s):

Ulcerative Colitis ◽

Gut Microbiota ◽

Bile Acids

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Gut microbiota composition and arterial stiffness measured by pulse wave velocity: case–control study protocol (MIVAS study)

BMJ Open ◽

10.1136/bmjopen-2020-038933 ◽

2021 ◽

Vol 11 (2) ◽

pp. e038933

Author(s):

Rita Salvado ◽

Sandra Santos-Minguez ◽

Cristina Agudo-Conde ◽

Cristina Lugones-Sanchez ◽

Angela Cabo-Laso ◽

...

Keyword(s):

Arterial Stiffness ◽

Gut Microbiota ◽

Pulse Wave Velocity ◽

Wave Velocity ◽

Intestinal Microbiota ◽

Pulse Wave ◽

Case Control Study ◽

Case Control ◽

Microbiota Composition ◽

Control Study

IntroductionIntestinal microbiota is arising as a new element in the physiopathology of cardiovascular diseases. A healthy microbiota includes a balanced representation of bacteria with health promotion functions (symbiotes). The aim of this study is to analyse the relationship between intestinal microbiota composition and arterial stiffness.Methods and analysisAn observational case—control study will be developed. Cases will be defined by the presence of at least one of the following: carotid-femoral pulse wave velocity (cf-PWV), Cardio-Ankle Vascular Index (CAVI), brachial ankle pulse wave velocity (ba or ba-PWV) above the 90th percentile, for age and sex, of the reference population. Controls will be selected from the same population as cases. The study will be developed in Primary Healthcare Centres. We will select 500 subjects (250 cases and 250 controls), between 45 and 74 years of age. Cases will be selected from a database that combines data from EVA study (Spain) and Guimarães/Vizela study (Portugal). Measurements: cf-PWV will be measured using the SphygmoCor system, CAVI, ba-PWV and Ankle-Brachial Index will be determined using VaSera device. Gut microbiome composition in faecal samples will be determined by 16S ribosomal RNA sequencing. Lifestyle will be assessed by food frequency questionnaire, adherence to the Mediterranean diet and IPAQ (International Physical Activity Questionnaire). Body composition will be evaluated by bioimpedance.Ethics and disseminationThe study has been approved by ‘Committee of ethics of research with medicines of the health area of Salamanca’ on 14 December 2018 (cod. 2018-11-136) and the ’Ethics committee for health of Guimaraes’ (Portugal) on 15 October 2019 (ref: 67/2019). All study participants will sign an informed consent form agreeing to participate in the study, in compliance with the Declaration of Helsinki and the WHO standards for observational studies. The results of this study will allow a better description of gut microbiota in patients with arterial stiffness.Trial registration detailsClinicalTrials.gov, identifier NCT03900338

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Endothelial Dysfunction and Low-Grade Inflammation Are Associated With Greater Arterial Stiffness Over a 6-Year Period

Hypertension ◽

10.1161/hypertensionaha.111.174557 ◽

2011 ◽

Vol 58 (4) ◽

pp. 588-595 ◽

Cited By ~ 82

Author(s):

Bas C. van Bussel ◽

Fleur Schouten ◽

Ronald M. Henry ◽

Casper G. Schalkwijk ◽

Michiel R. de Boer ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Arterial Stiffness ◽

Low Grade ◽

Low Grade Inflammation

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Relationships between Changing Gut Microbiota and the Pathogenesis of Fatty and Bile Acids in a Mouse Model of Non-Alcoholic Steatohepatitis

Journal of Hepatology ◽

10.1016/s0168-8278(16)01298-8 ◽

2016 ◽

Vol 64 (2) ◽

pp. S683

Author(s):

S. Yamada ◽

M. Watanabe ◽

H. Saito

Keyword(s):

Mouse Model ◽

Gut Microbiota ◽

Bile Acids ◽

Alcoholic Steatohepatitis

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Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽

10.1155/2009/501739 ◽

2009 ◽

Vol 2009 ◽

pp. 1-15 ◽

Cited By ~ 65

Author(s):

Tiangang Li ◽

John Y. L. Chiang

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Cholesterol Metabolism ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Cholesterol Homeostasis ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Major Pathway ◽

Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

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