Gut microbiota dysbiosis in adrenoleukodystrophy: a new piece in the puzzle?
- 1IDIBELL
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.
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BibTeX
@misc{torreni2026microbiota,
title = {{Gut microbiota dysbiosis in adrenoleukodystrophy: a new piece in the puzzle?}},
author = {L. Torreni and A. Schluter and S. Marti and M. Ruiz and V. Velez Santamaria and A. Rodriguez-Palmero and A. Artuch and C. Guilera and A. Arias and F. Mochel and S. Aguilera-Albesa and V. Cantarin and C. Casasnovas and R. Artuch and W. Koehler and A. Pujol and S. FOURCADE},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.26365873},
url = {https://www.medrxiv.org/content/10.64898/2026.10.19.26365873v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Gut microbiota dysbiosis in adrenoleukodystrophy: a new piece in the puzzle?
AU - L. Torreni
AU - A. Schluter
AU - S. Marti
AU - M. Ruiz
AU - V. Velez Santamaria
AU - A. Rodriguez-Palmero
AU - A. Artuch
AU - C. Guilera
AU - A. Arias
AU - F. Mochel
AU - S. Aguilera-Albesa
AU - V. Cantarin
AU - C. Casasnovas
AU - R. Artuch
AU - W. Koehler
AU - A. Pujol
AU - S. FOURCADE
PY - 2026
DA - 2026/10/19
PB - medRxiv
DO - 10.64898/2026.10.19.26365873
UR - https://www.medrxiv.org/content/10.64898/2026.10.19.26365873v1
AB - 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.
ER -