The Role of Bacterial Choline Metabolism in Host Stress Responses

胰岛素抵抗代表着美国迅速扩大的医疗负担，导致了许多心脏代谢性疾病的发病。最近出现的证据表明，寄居在人体肠道中的微生物是导致胰岛素抵抗和相关的心脏代谢性疾病的关键可传播环境因素。然而，肠道微生物衍生因子向宿主发出信号以促进胰岛素抵抗的机制在很大程度上尚不清楚。我们最近发现了一种代谢途径，在这种途径中，高脂肪食物中的营养物质(磷脂酰胆碱、胆碱和L肉碱)可以被肠道微生物酶代谢生成三甲胺，三甲胺再被宿主酶黄素单加氧酶3代谢生成三甲胺-N-氧化物(TMAO)。初步研究表明，在人类和动物模型中，TMAO途径与胰岛素抵抗和2型糖尿病的发生有关。此外，我们还表明，药物抑制TMAO的产生对小鼠的胰岛素抵抗具有显著的保护作用。从机制上讲，我们发现由糖皮质激素受体(GR)驱动的宿主代谢重编程需要FMO3的直接转录调节。总之，我们的初步数据使我们提出了以下中心假设：肠道微生物代谢产物TMAO是促进胰岛素抵抗的宿主应激反应的GR敏感介质。其具体目的是：目的1.验证肠道微生物TMAO途径直接影响高脂饮食驱动的胰岛素抵抗易感性的假设；以及目的2.确定宿主TMAO产生酶FMO3的转录调控是否对GR驱动的免疫抑制和代谢重编程是必要的。我们预计我们的研究将揭示肠道微生物衍生因子与胰岛素抵抗和相关的心脏代谢性疾病之间的新的分子机制，最终将被用于治疗2型糖尿病的第一种肠道微生物靶向疗法。

Insulin resistance represents a rapidly expanding health care burden in the United States, contributing to the pathogenesis of a number of cardiometabolic disorders. Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to insulin resistance and associated cardiometabolic disease. However, mechanisms by which gut microbial-derived factors signal to the host to promote insulin resistance are largely unknown. We have recently discovered a meta-organismal pathway where nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N- oxide (TMAO). Preliminary studies here demonstrate that the TMAO pathway is linked to insulin resistance and the development of type 2 diabetes in humans and animal models. Moreover, we show that pharmacologic inhibition of TMAO production confers striking protection against insulin resistance in mice. Mechanistically, we have found that host metabolic reprogramming driven by the glucocorticoid receptor (GR) requires direct transcriptional regulation of FMO3. Collectively, our preliminary data have led us to propose the following central hypothesis: The gut microbial metabolite TMAO is a GR-sensitive mediator of host stress responses that promote insulin resistance. The specific aims are: Aim 1. Testing the hypothesis that the gut microbial TMAO pathway directly impacts susceptibility for high fat diet-driven insulin resistance; and Aim 2. To determine whether transcriptional regulation of the host TMAO-producing enzyme FMO3 is necessary for GR-driven immunosuppression and metabolic reprogramming. We anticipate our studies to reveal new molecular mechanisms linking gut microbe-derived factors to insulin resistance and associated cardiometabolic disorder, which will ultimately be leveraged into to the first ever gut microbe-targeted therapeutics for the treatment of type 2 diabetes.