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

肠道微生物组在青少年神经性厌食症预后和治疗中的作用 - 临床和转化分析。

• 批准号: 509492174
• 负责人: Professor Dr. John F. Baines
• 金额: --
• 依托单位: Institut für Experimentelle Medizin (IEM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/509492174?language=en
• 关键词: role; intestinal; microbiome; regarding; prognosis

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.

神经性厌食症（AN）是女性青春期常见病，具有较强的遗传背景、高的慢性化率和病死率。目前的干预策略效果有限。持续的能量摄入不足，营养不良和激素变化会引起肠道微生物组的扰动，进而可能影响肠道-大脑的相互作用。在对女性AN患者（包括我们自己的患者）的初步研究中检测到大量肠道生态失调（改变的细菌分类群组成），这在体重增加后仅部分缓解。将AN患者的粪便移植到无菌（GF）青少年小鼠中，减少了后代的食物摄入量，食物利用率和年龄适当的体重增加，表明肠道微生物组在AN动物模型中的因果作用。连接肠道和大脑的机制包括迷走神经，可能增加肠道对细菌产物和部分的渗透性（“漏肠”），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的病理生理学中起着因果作用，从而有助于其维持和慢性化，甚至可能是其病因学。该提案的目标是使用我们现有的大型组合纵向患者人群，包括1年随访（N=91，430个样本），以研究AN中的微生物组-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对预测AN临床病程的预后价值。我们还将在1年随访时确定与良好结局特别相关的分类群，并培养这些细菌。使用经抗肿瘤治疗的基于翻译活性的厌食症（阿坝）大鼠模型，我们将移植来自AN患者的粪便，这些患者与健康对照组相比具有良好和不良的临床结果，以研究AN中肠道微生物组的因果影响。在第二步中，我们将施用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。肠道通透性、炎症、沿着大脑和行为变化的分析将补充这些研究。如果成功的话，这些细菌可能会被用于治疗。或者，它们的自然生长可以通过AN患者的营养干预来刺激。最终，针对微生物组的干预措施将为现有疗法提供新的和潜在的强大补充，以改善这种通常是慢性疾病的致残作用，并可能有助于克服它。