The role of the intestinal microbiome regarding prognosis and therapy in adolescent Anorexia nervosa – clinical and translational analyses.

神经性厌食症（Anorexia neurovosa， AN）是女性青春期常见病，具有较强的遗传背景和较高的致死率。目前的干预策略只是适度有效。持续的能量摄入不足、营养不良和激素改变会引起肠道微生物群的紊乱，并可能反过来影响肠-脑相互作用。在对女性AN患者（包括我们自己的患者）的初步研究中，发现了大量的肠道生态失调（细菌类群组成改变），这种情况在体重增加后只有部分缓解。将AN患者的粪便移植到无菌（GF）青春期小鼠中，可以减少后代的食物摄入量、食物利用率和与年龄相适应的体重增加，这表明肠道微生物组在AN动物模型中起着因果作用。连接肠道和大脑的机制包括迷走神经，可能增加肠道渗透性（“漏肠”）的产物和部分细菌，以及炎症和免疫过程。我们的总体假设是肠道微生物组在AN的病理生理中起因果作用，从而有助于其维持和慢性化，甚至可能是其病因。本提案的目标是利用我们现有的大型纵向合并患者群体，包括1年随访（N= 91,430个样本），研究AN中微生物组-肠-脑相互作用，作为更好地了解其在预后和治疗中的作用的第一步。为此，我们将确定影响肠道微生物组的因素在AN中的作用，以及入院时特定肠道微生物组组成的预后价值，以预测AN的临床病程。我们还将在1年的随访中确定与良好结果相关的分类群并培养这些细菌。使用抗生素治疗的基于转化活性的厌食症（ABA）大鼠模型，我们将移植临床结果良好和不良的an患者的粪便与健康对照，以研究肠道微生物组在an中的因果效应。在第二步中，我们将管理上述确定的特定分类群，以测试它们对动物体重变化和行为的因果影响。对肠道通透性、炎症以及大脑和行为变化的分析将补充这些研究。如果成功，这些细菌就有可能用于治疗。或者，可以通过对AN患者的营养干预来刺激它们的自然生长。最终，以微生物组为目标的干预措施将成为现有疗法的一种新的、潜在的强大补充，以改善这种通常是慢性疾病的致残效果，并可能有助于克服它。

Anorexia nervosa (AN) is a common disease in female adolescence with a strong genetic back-ground and high rates of chronicity and mortality. Current intervention strategies are only moderately effective. Persisting poor energy intake, undernutrition, and hormonal alterations give rise to perturbations of the gut microbiome and may in turn impact gut-brain interaction. A substantial intestinal dysbiosis (altered bacterial taxa composition) was detected in initial studies of female patients with AN – including our own – which was only in part alleviated after weight gain. Transplanting stool from patients with AN into germ-free (GF) adolescent mice reduced food intake, food utilization, and age-appropriate weight gain in the offspring, indicating a causal role of the gut microbiome in the AN animal model. Mechanisms linking the gut and the brain include the vagal nerve, probably increased intestinal permeability (“leaky gut”) of products and parts of bacteria, as well as inflammatory and immunologic processes. Our overarching hypothesis is that the gut microbiome plays a causal role in the pathophysiology of AN, thereby contributing to its maintenance and chronification and potentially even its etiology. The goal of this proposal is to use our large existing combined longitudinal patient populations including 1 year follow-up, (N=91, 430 samples) to investigate microbiome-gut-brain inter-actions in AN as a first step to better understanding its role in prognosis and therapy. To this end, we will determine the role of factors influencing the microbiome in AN and the prognostic value of specific gut microbiome composition at admission for prediction of the clinical course of AN. We will also identify taxa specifically associated with a good outcome at 1 year follow-up and cultivate these bacteria. Using an antibiotic-treated translational activity-based anorexia (ABA) rat model, we will transplant stool from patients with AN with good and poor clinical outcomes versus healthy controls in order to study causal effects of the gut microbiome in AN. In a second step, we will administer the above-identified specific taxa to test their causal influence on weight changes and behavior in the animals. Analysis of gut permeability, inflammation, along with brain and behavioral changes will complement these investigations. If successful, these bacteria can potentially be administered therapeutically. Alternatively, their natural growth can be stimulated via nutritional interventions in patients with AN. Ultimately, microbiome-targeted interventions would enable a new and potentially powerful addition to existing therapies to ameliorate the disabling effects of this often chronic disease and possibly help to overcome it.