Microbiome-mediated weight, anxiety, and stress dysregulation in anorexia nervosa

 描述（由申请人提供）：神经性厌食症（AN）是一种以极端体重失调为特征的精神疾病，通常伴有焦虑症。AN的治疗性营养主要基于临床意见和指南，证据基础薄弱。令人信服的数据表明肠道微生物群参与了肥胖和行为的调节，为探索这种复杂的微生物群落在AN的出现、维持和恢复中的作用提供了强有力的理论基础。我们的首要目标是了解肠道细菌导致AN患者肥胖、BMI、焦虑和压力失调的确切机制。我们推测，长期饥饿引起的肠道微生物群导致再喂养后肥胖增加，并导致AN患者焦虑和压力持续升高。为了验证我们的假设，我们提出了三个具体目标。在目标1中，我们将确定与AN患者的肥胖、BMI、焦虑和压力相关的肠道细菌群。我们将通过16S rRNA基因的高通量测序来表征急性低体重AN患者（T1）、体重恢复后相同患者（T2）和健康对照（HC）的肠道微生物群。我们将在本研究人群中比较特定肠道分类群与肥胖、BMI和行为（焦虑和压力）的丰度。在目标2中，我们将描述AN患者的肠道微生物群在移植到无菌（GF）小鼠中时对肥胖和BMI的功能影响。我们将从AN患者（T1和T2）和HC中移植未培养的微生物到GF小鼠中，并评估肠道微生物对肥胖的影响。在目标3中，我们将描述AN患者的肠道微生物群对焦虑和压力的功能影响，以及这些行为的分子生物标志物，当移植到GF小鼠中时。我们将T1 AN患者和HC的未培养微生物移植到GF小鼠中，并评估肠道微生物对焦虑和压力的影响。用无菌磷酸盐缓冲盐水管饲的GF小鼠将用作目标2和3中的对照。提出的科学在开创性地将基于16S rRNA基因测序的AN肠道微生物研究与探索其对肥胖的功能影响相结合方面具有重要意义 和与AN相关的行为特征。我们的研究结果将为如何最好地测试AN的辅助干预措施提供指导，包括益生菌，益生菌，抗生素或合生元，以增强目前的治疗体重恢复方法并改善治疗结果。这项科学具有高度创新性，因为它将研究AN中的一个全新因素，即肠道微生物群，并为我们提供一种新的方法来识别影响这种毁灭性疾病中肥胖和行为的肠道微生物。此外，我们将研究一个全新的因素（即肠道微生物群）作为AN潜在病理生理学的贡献者。

 DESCRIPTION (provided by applicant): Anorexia nervosa (AN), a psychiatric disorder characterized by extreme weight dysregulation commonly presents with comorbid anxiety. Therapeutic renourishment in AN is based primarily on clinical opinion and guidelines, with a weak evidence base. Compelling data implicate the intestinal microbiota in the regulation of adiposity and behavior, providing a strong rationale for exploring the role of this complex microbial community in the emergence and maintenance of, and recovery from AN. Our overarching goal is to understand the precise mechanism(s) by which intestinal bacteria contribute to dysregulation of adiposity, BMI, anxiety, and stress in patients with AN. We hypothesize that intestinal microbiotas that arise from prolonged starvation contribute to increases in adiposity upon refeeding and to persistently elevated anxiety and stress in individuals with AN. To test our hypothesis we propose 3 specific aims. In aim 1, we will identify the enteric bacterial groups associated with adiposity, BMI, anxiety, and stress in AN patients. We will characterize the intestinal microbiota in acutely low weight AN patients (T1), in the same patients following weight restoration (T2), and in healthy controls (HC) via high throughput sequencing of the 16S rRNA gene. We will compare the abundances of specific enteric taxa with adiposity, BMI and behavior (anxiety and stress) in this study population. In aim 2, we will characterize the functional impact of the intestinal microbiota of AN patients on adiposity and BMI when transplanted into germ free (GF) mice. We will transplant uncultured microbiotas from AN patients (at T1 and T2) and HC into GF mice and assess the impact of enteric microbes on adiposity. In aim 3, we will characterize the functional impact of the intestinal microbiota of AN patients on anxiety and stress, and molecular biomarkers of these behaviors, when transplanted into GF mice. We will transplant uncultured microbiotas from T1 AN patients and HC into GF mice and assess the impact of enteric microbes on anxiety and stress. GF mice gavaged with sterile phosphate buffer saline will be used as controls in aims 2 and 3. The proposed science is significant in pioneering the combination of large scale 16S rRNA gene sequencing-based studies of intestinal microbiotas in AN with exploration of their functional influence on adiposity and behavioral traits associated with AN. Our results will provide direction on how best to test adjunct interventions for AN with pre-, pro-, anti-, or syn-biotics to enhance current approaches to therapeutic weight restoration and improve treatment outcome. The science is highly innovative as it will investigate an entirely novel factor in AN, the intestinal microbiota, and us a novel approach to identify enteric microbes that impact adiposity and behavior in this devastating illness. Additionally, we will investigate an entirely novel factor (namely, the intestinal microbiota) as a contributor to the underlying pathophysiology of AN.