Year: 2026
Type: preprint
Study design: Observational Study
Abstract: ABSTRACT X-linked adrenoleukodystrophy (X-ALD) is the most common monogenic disorder affecting brain white matter, presenting a broad clinical spectrum from slowly progressive adrenomyeloneuropathy (AMN) to rapidly advancing cerebral demyelination. Factors influencing the variable disease expressivity remain poorly understood. We conducted shotgun metagenomic profiling of fecal samples from X-ALD patients and integrated these data with targeted plasma metabolomic analyses of amino acids and key metabolic intermediates. We identified distinct microbiome-associated metabolic signatures across X-ALD phenotypes. Notably, Bacteroides cellulosilyticus and Helicobacter apodemus abundance were significantly altered in AMN compared with childhood CALD patients. In parallel, X-ALD patients exhibited evidence of microbial metabolic remodeling characterized by altered amino acid metabolism, reduced folate biosynthetic potential, and enrichment of stress-adaptive pathways, including redox-associated functions, glyoxylate shunt activity, lipid A modification, lipopolysaccharide assembly, biofilm adhesin biosynthesis, and curli fiber production. Consistent with these microbial changes, plasma levels of branched-chain amino acids and methionine, as well as serum folate concentrations, were significantly reduced. Importantly, methionine levels showed an inverse correlation with neurofilament light chain (NfL) concentrations in patients with cerebral disease. Our findings reveal a previously unrecognized link between gut microbial metabolic capacity and systemic metabolic alterations in X-ALD. Our results reinforce previous evidence implicating methionine metabolism in disease severity. Collectively, these data support a modulatory role of the microbiota–gut–brain axis in neuroinflammatory and mitochondrial-related processes underlying X-ALD progression and highlight new opportunities for biomarker development and microbiome-informed therapeutic interventions.
Source: medRxiv
Authors: Lorenzo Torreni, Agatha Schlüter, Sara Marti, Montserrat Ruiz, Valentina Vélez-Santamaria, Agustí Rodríguez-Palmero, Ayelen Artuch, Cristina Guilera, Angela Arias, Fanny Mochel, Sergio Aguilera-Albesa, Veronica Cantarin, Carlos Casasnovas, Rafael Artuch, Wolfgang Köhler, Aurora Pujol, Stéphane Fourcade
Institutions: Institut d'Investigació Biomédica de Bellvitge, Centre for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Bellvitge University Hospital, Universitat de Barcelona, Universitat Autònoma de Barcelona, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Sant Joan de Déu, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Université Pierre-et-Marie-Curie, Navarrabiomed, Hospital Infantil Universitario Niño Jesús, University Hospital Leipzig, Institució Catalana de Recerca i Estudis Avançats
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223015404