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

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 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.