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

肠道微生物群在决定宿主代谢健康方面起着重要作用，主要是通过代谢物的产生。胆汁酸是最丰富和多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一个关键途径是共轭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：解偶联和7-α-去羟基化。我们发现，在不影响代谢的情况下，对肥胖患者进行来自瘦肉供体的粪便微生物群移植（FMT）治疗，可延缓与胆汁酸解结增加相关的葡萄糖耐受不良的发展。在一项补充研究中，我们发现在小鼠中补充膳食纤维可以改善葡萄糖代谢并增加肠道微生物7-α-去羟基化。然而，参与肠道微生物胆汁酸代谢的基因和细菌种类尚未完全确定，这限制了我们为未来临床试验改进FMT设计的能力。我们假设小鼠纤维补充和人类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，以响应纤维补充小鼠。为此，我们将对接受纤维或等热量饮食的高脂肪饮食小鼠的肠道微生物组进行宏基因组学和亚转录组学研究。此外，来自纤维和等热量处理组的宏基因组DNA将用于生成一个fosmid文库，该文库将被筛选以确定参与肠道微生物胆汁酸代谢的基因。在目标2中，我们将定义负责肠道微生物胆汁酸代谢的细菌种类和基因，以响应人类的FMT。为此，我们将对接受FMT或安慰剂治疗的患者的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查。这些数据将使未来的工作能够优化多模式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，用于2型糖尿病的治疗和预防。

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.