Anorexia nervosa (AN) can probably be regarded as a “model” for studying the interaction of nutrition with the gut–brain axis, which has drawn increased attention from researchers and clinicians alike. The gut microbiota influences somatic effects, such as energy extraction from food and body weight gain, as well as appetite, gut permeability, inflammation and complex psychological behaviors, such as depression or anxiety, all of which play important roles in AN. As nutrition is one of the main factors that influence the gut microbiota, nutritional restriction and selective eating in AN are likely influencing factors; however, nutritional rehabilitation therapy is surprisingly understudied. Here, we review the general mechanisms of the interactions between nutrition, the gut microbiota and the host that may be relevant to AN, paying special attention to the gut–brain axis, and we present the first specific findings in patients with AN and corresponding animal models. In particular, nutritional interventions, including food selection, supplements, and pre-, pro- and synbiotics that have the potential to influence the gut microbiota, are important research targets to potentially support future AN therapy.

Anorexia nervosa (AN) is a severe eating disorder that predominantly affects females and typically manifests during adolescence. There is increasing evidence that serum cytokine levels are altered in individuals with AN. Previous research has largely focused on adult patients, assuming a low-grade pro-inflammatory state. The serum levels of the cytokine tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-15, which are pro-inflammatory, were examined in 63 female adolescents with AN and 41 age-matched healthy controls (HC). We included three time points (admission, discharge, and 1-year follow-up) and investigated the clinical data to assess whether the gut microbiota was associated with cytokine alterations. Relative to the HC group, serum levels of IL-1β and IL-6 were significantly lower during the acute phase (admission) of AN. IL-1β expression was normalised to control levels after weight recovery. TNF-α levels were not significantly different between the AN and HC groups. IL-15 levels were significantly elevated in patients with AN at all time points. We found associations between cytokines and bodyweight, illness duration, depressive symptoms, and the microbiome. In contrast to most findings for adults, we observed lower levels of the pro-inflammatory cytokines IL-1β and IL-6 in adolescent patients, whereas the level of IL-15 was consistently increased. Thus, the presence of inflammatory dysregulation suggests a varied rather than uniform pro-inflammatory state.

Background: Anorexia nervosa (AN) is a severe psychiatric disease that often takes a chronic course due to insufficient treatment options. Emerging evidence on the gut-brain axis offers the opportunity to find innovative treatments for patients with psychiatric disorders. The gut microbiome of patients with AN shows profound alterations that do not completely disappear after weight rehabilitation. In previous studies, the administration of polyunsaturated fatty acids (PUFA) resulted in effects that might be beneficial in the treatment of AN, affecting the microbiome, body weight and executive functions. Therefore, the MiGBAN study aims to examine the effects of a nutritional supplementation with PUFA on the gut microbiome and body mass index (BMI) in patients with AN. Methods: This is a longitudinal, double-blind, randomized, placebo-controlled trial. Within 2 years, 60 adolescent patients aged 12 to 19 years with AN will receive either PUFA or placebo for 6 months additional to treatment as usual. After 1 year, the long-term effect of PUFA on the gut microbiome and consecutively on BMI will be determined. Secondary outcomes include improvement of gastrointestinal symptoms, eating disorder psychopathology, and comorbidities. Additionally, the interaction of the gut microbiome with the brain (microbiome-gut-brain axis) will be studied by conducting MRI measurements to assess functional and morphological changes and neuropsychological assessments to describe cognitive functioning. Anti-inflammatory effects of PUFA in AN will be examined via serum inflammation and gut permeability markers. Our hypothesis is that PUFA administration will have positive effects on the gut microbiota and thus the treatment of AN by leading to a faster weight gain and a reduction of gastrointestinal problems and eating disorder psychopathology. Discussion: Due to previously heterogeneous results, a systematic and longitudinal investigation of the microbiome-gut-brain axis in AN is essential. The current trial aims to further analyse this promising research field to identify new, effective therapeutic tools that could help improve the treatment and quality of life of patients. If this trial is successful and PUFA supplementation contributes to beneficial microbiome changes and a better treatment outcome, their administration would be a readily applicable additional component of multimodal AN treatment. Trial registration: German Clinical Trials Register DRKS00017130. Registered on 12 November 2019.

Objective: Patients with anorexia nervosa (AN) are often anxious, display inflexible behavior and disrupted reward processing. Emerging evidence suggests that gut dysbiosis in patients contributes to the disease phenotype and progression.Methods: In a preclinical study, we explored whether AN‐derived microbiota impacts cognitive flexibility, anxiety, and dopamine signaling using fecal microbiota transplantation (FMT) in tyrosine hydroxylase‐cre rats. We performed probabilistic reversal learning task (PRLT) at the baseline, after antibiotic treatment, and following FMT from patients with AN and controls. We assessed flexible behavior, task engagement, and ventral tegmental area (VTA) dopamine signaling during and in the absence of reward. Furthermore, anxiety‐like behavior was evaluated with open field (OF) and elevated plus maze (EPM) tests.Results: Neither antibiotic‐induced dysbiosis nor AN FMT led to significant alterations in the number of reversals or lever press strategies after reinforced or nonreinforced lever presses (win and lose‐stay) in the PRLT. However, the number of initiated trials decreased after antibiotic treatment while remaining unchanged after FMT. No significant differences were observed in VTA dopamine activity, anxiety measures in the OF and EPM tests. Microbiome analysis revealed limited overlap between the microbiota of the donors and recipients.Discussion: No evidence was found that the microbiota of patients compared to controls, nor a depleted microbiome impacts cognitive flexibility. Nonetheless, antibiotic‐induced dysbiosis resulted in reduced task engagement during the PRLT. The relatively low efficiency of the FMT is a limitation of our study and highlights the need for improved protocols to draw robust conclusions in future studies.Public Significance: While our study did not reveal direct impacts of AN‐associated gut microbiota on cognitive flexibility or anxiety behaviors in our preclinical model, we observed a decrease in task engagement after antibiotic‐induced dysbiosis, underscoring that the presence of a gut microbiome matters. Our findings underscore the need for further refinement in FMT protocols to better elucidate the complex interplay between gut microbiota and behaviors characteristic of anorexia nervosa.

Zusammenfassung: In den vergangenen Jahren ist ein deutlich zunehmendes Interesse an Darmmikrobiota und deren Interaktion mit dem Gehirn (Darm-Gehirn-Achse) zu beobachten. Dabei sind die bisher gewonnen Erkenntnisse der Mikrobiomforschung nicht nur für Grundlagenwissenschaftler_innen interessant, sondern bieten ebenfalls relevante Einsichten für die klinische Praxis. So erscheint ein kausaler Zusammenhang zwischen dem Darmmikrobiom und verschiedenen somatischen Erkrankungen wie Diabetes mellitus, chronisch entzündlichen Darmerkrankungen oder Adipositas, aber auch psychiatrischen Erkrankungen wie Depressionen, Angststörungen oder Essstörungen plausibel. Um den kausalen Zusammenhang der Darmbakterien mit einzelnen Phänotypen in Verbindung zu bringen, werden sogenannte Stuhltransplantationen (fäkale Mikrobiotatransplantationen) im präklinischen Kontext angewandt. Hierzu werden Mikrobiotaproben von Patient_innen in Versuchstiere transferiert, um mögliche Veränderungen des Phänotyps zu beobachten. Im klinischen Kontext werden fäkale Mikrobiotatransplantationen für erste Erkrankungen, zum Beispiel bei wiederkehrenden Infektionen mit Clostridioides difficile oder bei chronisch entzündlichen Darmerkrankungen bereits in der Therapie eingesetzt und sind bei ersterer bereits Teil der offiziellen Behandlungsleitlinien. Für viele weitere Erkrankungen, darunter auch psychische Erkrankungen, werden die Möglichkeiten der Anwendung von Stuhltransplantationen im Rahmen der Therapie derzeit verstärkt erforscht. Bisherige Erkenntnisse deuten darauf hin, dass das Darmmikrobiom und insbesondere fäkale Mikrobiotatransplantationen ein vielversprechender Ansatzpunkt für neue Therapien darstellt.