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Bile Acids

胆汁酸

基本信息

批准号：
10408684
负责人：
Kevin Michael Tveter
金额：
$ 3.59万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2023-03-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408684
关键词：
16S ribosomal RNA sequencing Agonist Anabolism Anaerobic Bacteria Antidiabetic Drugs Attenuated Bacteria Bile Acids Binding Body Weight CYP7A1 gene Cecum Ceramides Chenodeoxycholic Acid Cholestasis Cholesterol Chronic Chronic Disease Colon Consumption Data Diet Dietary Fats Dietary Intervention Dietary Polyphenol Digestion Duodenum Eating Enzymes Fibroblast Growth Factor Food G-Protein-Coupled Receptors GPBAR1 gene Gene Expression Genes Grapes Hepatic High Fat Diet Hyperglycemia Incubated Individual Inflammation Intestines Knockout Mice Lipopolysaccharides Liver LoxP-flanked allele Measures Mediating Membrane Metabolic Metabolic Diseases Metabolic syndrome Metformin Molecular Target Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Organoids Pathway interactions Proanthocyanidins Production Receptor Activation Receptor Inhibition Receptor Signaling Regulation Ribosomal RNA Risk Sampling Serum Signal Transduction Signaling Molecule Supplementation Synthetic Genes The Sun Therapeutic Intervention Tight Junctions Tissue Differentiation Tissues Triglyceride Metabolism Wild Type Mouse Work absorption antagonist bile acid metabolism bile acid transporter blood glucose regulation combat db/db mouse diabetic directed differentiation experimental study glucose metabolism glucose tolerance gut bacteria gut microbiota ileum improved insight insulin tolerance metabolic endotoxemia microbial community mouse model novel novel therapeutic intervention oral glucose tolerance polyphenol protein expression receptor resilience transcription factor

项目摘要

This proposal aims to elucidate how proanthocyanidin-rich extracts of grape polyphenols (GPs) modulate bile acid (BA) signaling to farnesoid X-receptor (FXR) resulting in improved glucose metabolism. Using intestine- specific (FxrΔIE) and liver-specific (FxrΔL) FXR knockout mice and derived ileal organoids, we will investigate whether GP-induced glycemic improvements are due to inhibition of intestinal and/or hepatic FXR signaling. We will also determine if GPs directly sequester secondary bile acids (SBAs) or indirectly leads to their depletion. Consumption of polyphenol-rich foods is associated with reduced risk of chronic disease; however, many dietary polyphenols are poorly absorbed raising questions about their mechanism(s) of action. Metabolic benefits of polyphenols are likely driven by changes in the gut microbiota. Prior work showed that GPs improved glucose metabolism in high-fat diet (HFD)-fed wild type (WT) mice due to GP-induced changes in the gut microbiota that correlated with attenuated body weight, metabolic endotoxemia (i.e. lower serum lipopolysaccharide (LPS)), tissue inflammation, as well as increased tight junction protein expression. Our recent data showed that GP supplementation mitigated hyperglycemia in diabetic db/db mice independent of changes in obesity, gut barrier integrity, and inflammation. Rather, GP-induced changes in the gut microbiota of db/db mice promoted a BA profile that suppressed intestinal FXR activity and FXR responsive pathways. Selective inhibition of intestinal FXR has been correlated with improved glucose metabolism and decreased ceramide synthesis in mice treated with antidiabetic drug, metformin. Metformin altered the gut microbiota and BA pool, reduced ceramide production, and lowered expression of hepatic gluconeogenic markers [Sun et al., 2018]. Dual antagonism of FXR in liver and intestine may promote cholestasis [Kong et al., 2012], therefore differentiating tissue specific effects of GPs on FXR activity is important. 16S rRNA V4 amplicon sequencing showed that GP supplementation depleted genera implicated in secondary BA (SBAs) metabolism concomitant with a dramatic decrease in serum SBAs and an increase in primary BAs (PBAs). Intestinal and liver tissues of mice supplemented with GPs had: 1) decreased gene expression of Shp and Fgf15, markers of FXR activity; 2) lowered expression of Smpd3, Cers4, and Sptlc2 , FXR responsive genes critical for ceramide synthesis; and 3) increased expression of Cyp7a1, an enzyme responsible for PBA synthesis. Gut organoids were used to differentiate the direct effects of BAs on intestinal FXR activation and ceramide synthesis and revealed GP-induced a BA profile antagonistic to intestinal FXR. We propose to 1) investigate glucoregulatory effect of GP supplementation in FxrΔIE and FxrΔL to uncover if GPs are antagonistic to liver FXR signaling mechanisms and distinguish the ability of GPs to sequester SBAs agonistic to FXR within the ileum. 2) Use ileal gut organoids derived from FXR∆IE to determine the requirement of intestinal FXR for GP-mediated regulation of ceramide biosynthesis and 3) directly determine whether anaerobic cultures of ileal content collected from GP supplemented mice lack ability to produce SBAs.

本研究旨在阐明富含原花青素的葡萄多酚提取物如何调节胆汁酸（BA）信号传导至法尼醇X-受体（FXR），导致改善的葡萄糖代谢。利用肠子- 特异性（FxrΔIE）和肝脏特异性（FxrΔL）FXR敲除小鼠和衍生的回肠类器官，我们将研究 GP诱导的血糖改善是否是由于肠和/或肝FXR信号传导的抑制。我们还将确定GP是否直接螯合二级胆汁酸（SBA）或间接导致其耗尽。食用富含多酚的食物与降低慢性疾病的风险有关;然而，许多饮食多酚的吸收较差，这引起了关于其作用机制的问题。代谢益处多酚可能是由肠道微生物群的变化驱动的。先前的研究表明，全科医生改善葡萄糖由于GP诱导的肠道微生物群的变化，与体重减轻、代谢性内毒素血症（即血清脂多糖（LPS）降低）、组织炎症以及紧密连接蛋白表达增加。我们最近的数据显示，补充可减轻糖尿病db/db小鼠高血糖，与肥胖、肠屏障完整性和炎症相反，GP诱导的db/db小鼠肠道微生物群的变化促进了BA 抑制肠道FXR活性和FXR应答途径的特征。选择性肠抑制 FXR与治疗小鼠的葡萄糖代谢改善和神经酰胺合成减少相关抗糖尿病药物二甲双胍代谢物改变了肠道微生物群和BA池，减少了神经酰胺产生，并降低肝致坏死标志物的表达[Sun等人，2018年]。双重拮抗肝和肠中的FXR可促进胆汁淤积[Kong等人，2012年]，因此区分组织特异性 GP对FXR活性的影响是重要的。16 S rRNA V4扩增子测序显示，GP补充与次级BA（SBAs）代谢有关的耗尽的属伴随着血清中BA水平的急剧下降， SBAs和主要BA（PBAs）的增加。补充GP的小鼠的肠道和肝脏组织具有： 1)FXR活性标志物Shp和Fgf 15的基因表达降低; 2）Smpd 3的表达降低， Cers 4和Sptlc 2，对神经酰胺合成至关重要的FXR应答基因;和3）增加的 Cyp 7a 1，一种负责PBA合成的酶。肠道类器官用于区分直接作用的BA对肠道FXR激活和神经酰胺合成的影响，并揭示了GP诱导的BA拮抗作用。肠道FXR。我们的研究目的是：1）研究GP对FxrΔIE和FxrΔL的糖调节作用揭示GPs是否拮抗肝脏FXR信号传导机制，并区分GPs 将对FXR激动的SBA隔离在回肠内。2)使用源自FXR消化道的回肠肠类器官来确定肠FXR对GP介导调节神经酰胺生物合成的需要，以及3）直接确定从补充GP的小鼠收集的回肠内容物的厌氧培养物是否缺乏产生SBA的能力。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Grape Polyphenols May Prevent High-Fat Diet-Induced Dampening of the Hypothalamic-Pituitary-Adrenal Axis in Male Mice.

DOI：
10.1210/jendso/bvad095
发表时间：
2023-08-01
期刊：
JOURNAL OF THE ENDOCRINE SOCIETY
影响因子：
4.1
作者：
Mezhibovsky, Esther;Tveter, Kevin M.;Villa-Rodriguez, Jose A.;Bacalia, Karen;Kshatriya, Dushyant;Desai, Nikhil;Cabales, Alrick;Wu, Yue;Sui, Ke;Duran, Rocio M.;Bello, Nicholas T.;Roopchand, Diana E.
通讯作者：
Roopchand, Diana E.

Impact of grape polyphenols on Akkermansia muciniphila and the gut barrier.