Mapping bile acid metabolism across the gut microbiome in response to dietary fiber

绘制肠道微生物组胆汁酸代谢对膳食纤维的反应

基本信息

批准号：
10618421
负责人：
Bethany Paige Cummings
金额：
$ 15.89万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618421
关键词：
Bile Acids Biology Body Weight decreased CYP2C19 gene Clinical Trials Combined Modality Therapy DNA Data Development Diet Dietary Fiber Epidemic Fiber Future Gene Expression Genes Glucose Intolerance Health High Fat Diet Human Knockout Mice Libraries Metabolic Metagenomics Mus Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Placebo Control Placebos Play Prevalence Prevention Probability Probiotics Process Production Randomized Regulation Research Role Sampling Secondary to Supplementation System Testing Thinness Time Validation Work bile acid metabolism blood glucose regulation capsule comparative dehydroxylation design fecal transplantation feeding gene function glucose metabolism gut microbes gut microbiome improved metatranscriptomics microbial minimally invasive multimodality novel obese patients obesity treatment pilot trial prebiotics research clinical testing response side effect targeted treatment

项目摘要

The gut microbiome plays an important role in determining host metabolic health, largely through the production of metabolites. Bile acids are one of the most abundant and variable gut microbial metabolites; however, the details of gut microbial bile acid metabolism remain poorly understood. A key pathway in gut microbial bile acid metabolism is the conversion of conjugated primary bile acids to secondary bile acids. This is a multi-step process that can be distilled down to two key steps: deconjugation and 7-α-dehydroxylation. We have found that treatment of patients with obesity, but without metabolic compromise, with fecal microbiota transplantation (FMT) derived from a lean donor delays the development of glucose intolerance which is associated with increased bile acid deconjugation. In a complementary line of research, we have found that dietary fiber supplementation in mice improves glucose metabolism and increases gut microbial 7-α-dehydroxylation. However, the genes and bacterial species involved in gut microbial bile acid metabolism are incompletely defined, which limits our ability to refine our FMT design for future clinical testing. We hypothesize that fiber supplementation in mice and FMT in humans alters gut microbial bile acid metabolism through novel bacterial species and/or genes. In aim 1, we will define the bacterial species and genes responsible for gut microbial bile acid metabolism in response to fiber supplementation in mice. To this end, we will perform metagenomics and metatranscriptomics of the gut microbiome from high fat diet-fed mice receiving fiber or an isocaloric diet. Further, metagenomic DNA from fiber- and isocaloric-treated groups will be used to generate a fosmid library which will be screened to identify the genes involved in gut microbial bile acid metabolism. In aim 2, we will define the bacterial species and genes responsible for gut microbial bile acid metabolism in response to FMT in humans. To this end, we will perform metagenomics, metatranscriptomics and a functional metagenomics screen on fecal samples from patients receiving FMT or placebo. These data will enable future work to optimize multimodal FMT, prebiotic and probiotic combination therapies aimed at enhancing gut microbial bile acid metabolism for type 2 diabetes treatment and prevention.

肠道微生物组在决定宿主代谢健康方面发挥着重要作用，主要是通过代谢物的产生来实现的。胆汁酸是最丰富且可变的肠道微生物代谢物之一；然而，肠道微生物胆汁酸代谢的细节仍然知之甚少。肠道微生物胆汁酸代谢的途径是将结合的初级胆汁酸转化为次级胆汁酸，这是一个多步骤的过程，可以归结为两个关键步骤：解结合和我们发现，通过来自瘦供者的粪便微生物群移植（FMT）治疗肥胖患者，但不会影响代谢，可延缓与胆汁酸解结合增加相关的葡萄糖不耐受的发生。补充研究线，我们发现补充膳食纤维可以改善小鼠的葡萄糖代谢并增加肠道微生物7-α-脱羟基，但是参与肠道微生物胆汁酸代谢的基因和细菌种类并不完全。定义，这限制了我们为未来的临床测试完善 FMT 设计的能力。我们发现，小鼠中的纤维补充和人类中的 FMT 通过新的细菌种类和/或基因改变肠道微生物胆汁酸代谢。在目标 1 中，我们将定义负责小鼠肠道微生物胆汁酸代谢的细菌种类和基因，以响应纤维补充。为此，我们将对接受纤维或纤维的高脂肪饮食喂养的小鼠的肠道微生物组进行宏基因组学和宏转录组学。此外，来自纤维和等热量处理组的宏基因组DNA将用于生成fosmid文库，该文库将被筛选以鉴定参与肠道微生物胆汁酸代谢的基因。在目标2中，我们将定义细菌种类和为此，我们将对患者粪便样本进行宏基因组学、宏转录组学和功能宏基因组学筛选。这些数据将使未来能够优化多模式 FMT、益生元和益生菌联合疗法，旨在增强肠道微生物胆汁酸代谢，以治疗和预防 2 型糖尿病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impact of fecal microbiota transplantation with capsules on the prevention of metabolic syndrome among patients with obesity.

DOI：
10.1007/s42000-020-00265-z
发表时间：
2021-03
期刊：
Hormones (Athens, Greece)
影响因子：
0
作者：
Allegretti JR;Kassam Z;Hurtado J;Marchesi JR;Mullish BH;Chiang A;Thompson CC;Cummings BP
通讯作者：
Cummings BP

Impact of Fecal Microbiota Transplantation on Gut Bacterial Bile Acid Metabolism in Humans.