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

肠道微生物组在决定宿主代谢健康方面起着重要作用，主要是通过产生代谢物。胆汁酸是最丰富和可变的肠道微生物代谢产物之一;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关键途径是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：去缀合和7-α-脱羟基。我们已经发现，用来自瘦供体的粪便微生物群移植（FMT）治疗肥胖但没有代谢损害的患者延迟了与增加的胆汁酸去缀合相关的葡萄糖耐受不良的发展。在一项补充研究中，我们发现膳食纤维补充剂可以改善小鼠的葡萄糖代谢，并增加肠道微生物7-α-脱羟基作用。然而，参与肠道微生物胆汁酸代谢的基因和细菌物种还没有完全确定，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，在小鼠和FMT在人类中的纤维补充剂通过新的细菌物种和/或基因改变肠道微生物胆汁酸代谢。在目标1中，我们将确定负责肠道微生物胆汁酸代谢的细菌种类和基因，以响应小鼠中的纤维补充。为此，我们将对接受纤维或等热量饮食的高脂肪饮食喂养小鼠的肠道微生物组进行宏基因组学和元转录组学研究。此外，来自纤维和等热量处理组的宏基因组DNA将用于产生fosmid文库，其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，我们将确定负责肠道微生物胆汁酸代谢的细菌种类和基因，以响应人类中的FMT。为此，我们将对接受FMT或安慰剂的患者的粪便样本进行宏基因组学、元转录组学和功能性宏基因组学筛查。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.