The impact of soft-fruit phytochemicals on the gut microbiome and bile acid metabolism

软果植物化学物质对肠道微生物组和胆汁酸代谢的影响

• 批准号: 2440932
• 金额: --
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2440932
• 关键词: impact; soft; fruit; phytochemicals; gut

Bile acid metabolism is a critical component of the digestion process. Bile acids emulsify dietary lipids to prepare them for enzymatic digestion into glycerol and fatty acids and subsequent absorption into the gut epithelium. Intestinal bile acid concentrations are under a feedback loop control of the enterohepatic cycle. This is possible because bile acids also act as signalling molecules throughout the gut. An increase in bile acids, and hence bile acid signalling, leads to an increase in FGF15/19 expression and secretion, which in turn reduces expression of the key bile acid synthesis gene Cyp7A1.Disturbance of bile acid synthesis by either overexpressing or inactivating the key enzyme Cyp7A1 in transgenic animals dramatically reduces nutrient uptake and generates resistance to obesity but has significant side-effects. However smaller modulations of bile acid activity can have beneficial effects on metabolic health. Bile acids are synthesized in the liver, stored in the gallbladder and released in response to food intake. As part of the synthesis process bile acids are conjugated to amino acids to increase their solubility. Microbial enzymes modulate the composition of the bile acid pool, e.g. through bile salt hydrolase which removes the amino acid moiety, altering the biological signalling effects of bile acids.We have recently shown that blueberry extracts have a strong anti-obesogenic effect in mice. This is associated with a dramatic shift in both, intestinal bile acid and microbiome composition. At present we do not know whether the two effects are dependent on each other, and if so which one of the changes is causal. We have also shown changes in bile acid composition in response to soft-fruit supplementation in human intervention trials suggesting that the health benefits seen in rodents can be translated into the human situation.The proposed project seeks to assess the interaction of soft fruit phytochemicals with the gut microbiota and bile acid metabolism using a combination of experiments in animal model systems, in vitro models of microbial digestion, and human intervention trials.[1] We will test the effects of plant secondary metabolites on the composition and relevant enzymatic activities of human and rodent microbiomes. This will be done using in vitro experiments using anaerobic microbiological fermentors and, in vivo, using ileal, and faecal samples from rodent and human experiments. Microbiome composition will be tested using next generation sequencing. [2] The effect of different microbiomes on bile acid composition will be studied in vitro and in rodent model systems. Bile acid composition will be measured using mass spectrometry, HPLC and microbiological assays. [3] Expression of genes responsive to bile acid signalling will be analysed in liver, gut and adipose cell lines (and cell-based assay systems based on them) and rodent tissue samples. These data will assess the consequences of bile acid composition on signalling pathways relevant to metabolic health.

胆汁酸代谢是消化过程的重要组成部分。胆汁酸使膳食脂肪乳化，使其易于酶促消化成甘油和脂肪酸，随后被肠道上皮吸收。肠道胆汁酸浓度受肠肝循环的反馈回路控制。这是可能的，因为胆汁酸也在整个肠道中充当信号分子。胆汁酸和胆汁酸信号传导的增加导致FGF15/19的表达和分泌增加，进而降低关键胆汁酸合成基因Cyp7A1的表达。在转基因动物中，通过过表达或失活关键酶Cyp7A1来干扰胆汁酸合成可显著降低营养摄取并产生肥胖抗性，但具有显著的副作用。然而，胆汁酸活性的较小调节可以对代谢健康产生有益影响。胆汁酸在肝脏中合成，储存在胆囊中，并随着食物摄入而释放出来。作为合成过程的一部分，胆汁酸与氨基酸结合以增加其溶解度。微生物酶调节胆汁酸池的组成，例如通过去除氨基酸部分的胆盐水解酶，改变胆汁酸的生物信号效应。我们最近表明，蓝莓提取物对小鼠有很强的抗肥胖作用。这与肠道胆汁酸和微生物组组成的巨大变化有关。目前我们还不知道这两种影响是否相互依赖，如果是的话，哪一种变化是因果关系。我们还在人体干预试验中显示了对软果补充剂的胆汁酸组成的变化，这表明在啮齿动物身上看到的健康益处可以转化为人类的情况。该项目旨在通过动物模型系统实验、体外微生物消化模型和人为干预试验，评估软果植物化学物质与肠道微生物群和胆汁酸代谢的相互作用我们将测试植物次生代谢物对人类和啮齿动物微生物组组成和相关酶活性的影响。这将使用厌氧微生物发酵罐进行体外实验，并使用来自啮齿动物和人类实验的回肠和粪便样本进行体内实验。微生物组组成将使用下一代测序进行测试。不同微生物组对胆汁酸组成的影响将在体外和啮齿动物模型系统中进行研究。胆汁酸组成将使用质谱法、高效液相色谱法和微生物测定法进行测定。[3]将在肝脏、肠道和脂肪细胞系（以及基于它们的细胞检测系统）和啮齿动物组织样本中分析胆汁酸信号反应基因的表达。这些数据将评估胆汁酸组成对代谢健康相关信号通路的影响。