Comparison of gallstone dissolution between single ursodeoxycholic acid, ursodioxycholic acid and N-3 polyunsaturated fatty acids in gallstone gallstone patients: investigator-led, Single research institute, randomization Study, Phase II Clinical Trial.

开始日期2020-03-16

申办/合作机构-

NCT01931241 / Unknown status临床1期

Phase I Randomized Placebo Controlled Double Blind SAD and MAD Study of Oral AHRO-001 to Assess Safety, Tolerability &PK in Volunteers w/Mild/Moderate Hypercholesteremia

Preclinical data support the hypothesis that the administration of AHRO-001 reduces LDL cholesterol levels, improves HDL function, and finally, decreases atheromatous plaque burden.

开始日期2013-06-01

申办/合作机构

AtheroNova, Inc.

100 项与猪去氧胆酸相关的临床结果

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100 项与猪去氧胆酸相关的转化医学

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100 项与猪去氧胆酸相关的专利（医药）

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230

项与猪去氧胆酸相关的文献（医药）

2024-12-31·Gut Microbes

Paclitaxel chemotherapy disrupts microbiota-enterohepatic bile acid metabolism in mice

Article

作者: Rogers, Lynette K. ; Loman, Brett R. ; Bailey, Michael T. ; Alzoubi, Zainab ; Grant, Corena V. ; Jordan, Kelley ; Lynch, Alexis J. ; Jaggers, Robert M. ; Pyter, Leah M.

Balanced interactions between the enteric microbiota and enterohepatic organs are essential to bile acid homeostasis, and thus normal gastrointestinal function. Disruption of these interactions by cancer treatment instigates bile acid malabsorption, leading to treatment delays, malnutrition, and decreased quality of life. However, the nature of chemotherapy-induced bile acid malabsorption remains poorly characterized with limited treatment options. Therefore, this study sought to characterize changes in hepatic, enteric, and microbial bile acid metabolism in a mouse model of chemotherapy-induced toxicity. Consistent with clinical bile acid malabsorption, chemotherapy increased fecal excretion of primary bile acids and water, while diminishing microbiome diversity, secondary bile acid formation, and small intestinal bile acid signaling. We identified new contributors to pathology of bile acid malabsorption in the forms of lipopolysaccharide-induced cholestasis and colonic crypt hyperplasia from reduced secondary bile acid signaling. Chemotherapy reduced markers of hepatic bile flow and bile acid synthesis, elevated markers of fibrosis and endotoxemia, and altered transcription of genes at all stages of bile acid metabolism. Primary hepatocytes exposed to lipopolysaccharide (but not chemotherapy) replicated chemotherapy-induced transcriptional differences, while gut microbial transplant into germ-free mice replicated very few differences. In the colon, chemotherapy-altered bile acid profiles (particularly higher tauromuricholic acid and lower hyodeoxycholic acid) coincided with crypt hyperplasia. Exposing primary colonoids to hyodeoxycholic acid reduced proliferation, while gut microbiota transplant enhanced proliferation. Together, these investigations reveal complex involvement of the entire microbiota-enterohepatic axis in chemotherapy-induced bile acid malabsorption. Interventions to reduce hepatic lipopolysaccharide exposure and enhance microbial bile acid metabolism represent promising co-therapies to cancer treatment.

2024-10-01·Cell Reports

Gut Bacteroides ovatus ameliorates renal fibrosis by promoting the production of HDCA through upregulation of Clostridium scindens

Article

作者: Liu, Hui-Ling ; Huang, Zhou ; Wang, Yin-Yin ; Li, Qing-Zhen ; Ma, Gao-Xiang ; Wang, Tao ; Li, Jun-Hui ; Zhang, Zhi-Hao ; Cao, Yi-Zhi ; Li, Jing ; Tan, Ya-Jie ; Yan, Miao ; Liu, Hong-Wei ; Huang, Feng-Qing ; Alolga, Raphael N ; Wang, Han-Yu ; Si, Zi-Lin ; Liu, Kang ; Chen, Cheng

Renal fibrosis, inflammation, and gut dysbiosis are all linked to chronic kidney disease (CKD). Here we show that Bacteroides ovatus protects against renal fibrosis. Mechanistically, B. ovatus enhances intestinal hyodeoxycholic acid (HDCA) levels by upregulating a strain of intestinal bacteria, Clostridium scindens, that has the capacity for direct HDCA production in mice. HDCA significantly promoted GLP-1 secretion by upregulating the expression of TGR5 and downregulating the expression of farnesoid X receptor (FXR) in the gut. Activation of renal GLP-1R attenuates renal fibrosis while delaying the subsequent development of CKD. In addition, HDCA can also protect against renal fibrosis by directly upregulating renal TGR5. The natural product neohesperidin (NHP) was found to exert its anti-renal fibrotic effects by promoting the growth of B. ovatus. Our findings provide mechanistic insights into the therapeutic potential of B. ovatus, C. scindens, and HDCA in treating CKD.

2024-08-01·CHEMICO-BIOLOGICAL INTERACTIONS

Ex vivo metabolism kinetics of primary to secondary bile acids via a physiologically relevant human faecal microbiota model

Article

作者: Ong, Jia Hui ; Tan, Amanda Jia Hui ; Low, Adrian ; Chan, Eric Chun Yong ; Kwa, Wit Thun ; Ng, Daniel Zhi Wei ; Lee, Jonathan Wei Jie

Bile acids (BA) are synthesized in the human liver and undergo metabolism by host gut bacteria. In diseased states, gut microbial dysbiosis may lead to high primary unconjugated BA concentrations and significant perturbations to secondary BA. Hence, it is important to understand the microbial-mediated formation kinetics of secondary bile acids using physiologically relevant ex vivo human faecal microbiota models. Here, we optimized an ex vivo human faecal microbiota model to recapitulate the metabolic kinetics of primary unconjugated BA and applied it to investigate the formation kinetics of novel secondary BA metabolites and their sequential pathways. We demonstrated (1) first-order depletion of primary BA, cholic acid (CA) and chenodeoxycholic acid (CDCA), under non-saturable conditions and (2) saturable Michaelis-Menten kinetics for secondary BA metabolite formation with increasing substrate concentration. Notably, relatively lower Michaelis constants (K_m) were associated with the formation of deoxycholic acid (DCA, 14.3 μM) and lithocholic acid (LCA, 140 μM) versus 3-oxo CA (>1000 μM), 7-keto DCA (443 μM) and 7-keto LCA (>1000 μM), thereby recapitulating clinically observed saturation of 7α-dehydroxylation relative to oxidation of primary BA. Congruently, metagenomics revealed higher relative abundance of functional genes related to the oxidation pathway as compared to the 7α-dehydroxylation pathway. In addition, we demonstrated gut microbial-mediated hyocholic acid (HCA) and hyodeoxycholic acid (HDCA) formation from CDCA. In conclusion, we optimized a physiologically relevant ex vivo human faecal microbiota model to investigate gut microbial-mediated metabolism of primary BA and present a novel gut microbial-catalysed two-step pathway from CDCA to HCA and, subsequently, HDCA.

项与猪去氧胆酸相关的新闻（医药）

2023-08-18

·生物谷

Cell子刊：贾伟/郑晓皎/贾伟平团队揭示猪去氧胆酸通过调控肠肝轴治疗非酒精性脂肪性肝病的机制

综上所述，该研究阐明了猪去氧胆酸（HDCA）通过肠（肠道菌群与肠道FXR信号通路）-肝脏（CYP7B1、PPARα）轴缓解肝脏脂质堆积，改善非酒精性脂肪性肝病（NAFLD）的分子机制上海交通大学医学院附属第六人民医院贾伟、郑晓皎、贾伟平教授团队在 Cell Metabolism 期刊发表了题为：Hyodeoxyholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis 的研究论文。该研究揭示了猪去氧胆酸通过肠肝轴治疗非酒精性脂肪性肝病（NAFLD）的新机制，也为其提供了潜在的靶点与干预手段。研究人员对非酒精性脂肪性肝病临床队列以及饮食诱导小鼠模型的血清/肝脏样本进行胆汁酸靶向代谢组学分析，结果发现猪去氧胆酸（hyodeoxycholic acid，HDCA）随着疾病的进展逐渐降低，且与代谢性指标呈显著负相关。进一步，研究人员用HDCA干预多种非酒精性脂肪性肝病模型小鼠（饮食诱导、基因敲除），发现肝脏脂质堆积、炎症、纤维化均得到显著的缓解。为了探究HDCA缓解肝脏脂质代谢的分子机制，利用转录组测序分析方法，研究人员发现肝脏胆汁酸替代合成途径合成酶-CYP7B1显著上调，而经典途径合成酶-CYP7A1显著下调。胆汁酸替代合成途径已被证明在调节机体代谢中发挥着至关重要的作用。进一步，对小鼠模型的肝脏CYP7B1进行干预，证明CYP7B1是HDCA发挥作用的一个关键靶点。那么HDCA是如何影响这两个酶的表达？首先，基于前期实验结果，研究人员先发现了HDCA可以显著抑制肠道FXR信号通路。有趣的是，单纯抑制肠道FXR信号通路，并不能复现肝脏CYP7A1显著下调的结果，因此研究人员猜测可能存在其他因素在发挥作用。利用宏基因组测序分析、粪菌移植等方法，研究人员发现了一种益生菌——狄氏副拟杆菌（Parabacteroides distasonis）在HDCA干预后丰度显著增高，体外实验证明HDCA可以直接促进狄氏副拟杆菌的生长。狄氏副拟杆菌是如何介导调控肝脏胆汁酸合成酶？基于肝脏转录学测序结果，研究人员发现PPAR信号通路在HDCA干预后显著上调，结合代谢组学检测，最终研究人员确定一种长链多不饱和脂肪酸——γ亚麻酸，在HDCA干预后显著增加。进一步，研究人员通过体外细胞实验、荧光素酶报告基因实验确定了γ亚麻酸通过激活PPARα下调CYP7A1的表达。综上所述，该研究阐明了猪去氧胆酸（HDCA）通过肠（肠道菌群与肠道FXR信号通路）-肝脏（CYP7B1、PPARα）轴缓解肝脏脂质堆积，改善非酒精性脂肪性肝病（NAFLD）的分子机制，为代谢性疾病中多器官对话的机制性研究提供了新的理论依据，同时为非酒精性脂肪性肝病的防治提供了新的干预策略。上海交通大学医学院附属第六人民医院贾伟教授、郑晓皎教授、贾伟平院士为改论文共同通讯作者，上海交通大学医学院博士研究生况俊良为论文第一作者。