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，主要是通过代谢产物的产生。胆汁酸是肠道微生物代谢产物中含量最丰富、种类最多的一种，然而，有关肠道微生物胆汁酸代谢的细节仍知之甚少。肠道微生物胆汁酸代谢的一个关键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，可以蒸馏成两个关键步骤：去共轭和7-α-脱羟基。我们发现，在不影响代谢的情况下，使用来自瘦肉供者的粪便微生物区系移植(FMT)治疗肥胖症患者可以延缓与胆汁酸去结合增加相关的葡萄糖耐量的发展。在一系列补充研究中，我们发现补充膳食纤维改善了小鼠的葡萄糖代谢，并增加了肠道微生物7-α-脱羟基。然而，参与肠道微生物胆汁酸代谢的基因和细菌种类还没有完全确定，这限制了我们改进FMT设计用于未来临床测试的能力。我们假设，小鼠的纤维补充和人类的FMT通过新的细菌物种和/或基因改变肠道微生物胆汁酸的代谢。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等卡路里饮食的高脂饮食小鼠的肠道微生物组进行元基因组学和元转录组学研究。此外，来自纤维和等卡路里处理组的超基因组DNA将被用来生成一个Fosid文库，该文库将被筛选以识别与肠道微生物胆汁酸代谢有关的基因。在目标2中，我们将定义负责人类肠道微生物胆汁酸代谢的细菌种类和基因，以响应FMT。为此，我们将对接受FMT或安慰剂的患者的粪便样本进行元基因组学、元转录组学和功能元基因组学筛查。这些数据将使未来的工作能够优化多模式FMT、益生菌和益生菌组合疗法，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.