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

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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.