Anorexia nervosa (AN) is associated with profound alterations in gut microbiota and host metabolic profiles. While previous studies have primarily focused on the acute phase of AN, the chronic form, severe and enduring anorexia nervosa (SEAN), remains underexplored in terms of microbiome dynamics. In this study, we characterized gut microbiota composition (via 16S rRNA gene amplicon sequencing), serum and fecal metabolites (via mass spectrometry), and an extensive range of clinical, anthropometric, biochemical, and psychiatric parameters in females with acute AN, SEAN, and in healthy controls. SEAN patients exhibited higher antidepressant usage and greater lifetime stress exposure. Acute AN patients presented with more pronounced eating disorder severity and depressive symptoms. Elevated levels of intestinal fatty acid-binding protein in SEAN patients suggest mucosal damage. Microbiota analysis revealed reduced alpha diversity and distinct community composition in both AN groups, with SEAN showing the greatest interindividual variability. Both AN cohorts exhibited significantly lower serum and fecal γ-aminobutyric acid (GABA) levels, which were negatively correlated with taxa such as Christensenellaceae, Ruminococcaceae, and Escherichia-Shigella, i.e., microorganisms potentially associated with GABA degradation or impaired synthesis. Additionally, reductions in short-chain fatty acids suggest impaired microbial fermentation and dysregulation of the gut-brain axis. Collectively, these findings reveal progressive, functionally relevant changes in microbiota-host interactions in SEAN. These alterations likely reflect the persistent disease state and may contribute to its continuation.

1st Faculty of Medicine Charles University Prague 2 Czech Republic

Department of Psychiatry 1st Faculty of Medicine Charles University and General University Hospital Prague Prague 2 Czech Republic

Faculty of Science Department of Zoology Charles University Prague 2 Czech Republic

Institute for Environmental Studies Faculty of Science Charles University Prague 2 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Prague 4 Czech Republic

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