Exploratory Metabolomic and Metagenomic Profiling of Fecal Samples in Isolated REM Sleep Behavior Disorder
6 affiliations
- 1IRCCS, Istituto delle Scienze Neurologiche di Bologna, Laboratorio di Proteomica Metabolomica e Chimica Bioanalitica, 40139 Bologna, Italy
- 2Department of Biomedical and Neuromotor Sciences, University of Bologna, 40123 Bologna, Italy
- 3IRCCS, Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
- 4Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
- 5Occupational Medicine Unit, DIMEC, University of Bologna, 40138 Bologna, Italy
- 6Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy
Abstract
Isolated REM sleep behavior disorder (iRBD) is among the most reliable prodromal markers of α-synucleinopathies. Under the body-first (gut-first) model of α-synuclein pathology, in which pathology may originate in the enteric nervous system and ascend to the brain, the gut is a biologically plausible compartment in which early and accessible molecular alterations might be detectable; however, the fecal metabolome remains poorly investigated in this population. In this exploratory, cross-sectional study of 21 iRBD patients and 15 healthy controls, we characterized fecal samples through an integrated multi-omics framework. The fecal metabolome was profiled on two complementary mass spectrometry platforms: HS-SPME GC-EI-high-resolution MS, used for both untargeted volatilomics and targeted quantification of linear and branched short-chain fatty acids, and untargeted LC-MS/MS for the non-volatile fraction. Gut microbial community composition was characterized on the same material by 16S rRNA gene sequencing, and the metabolomic and microbial layers were combined by DIABLO multi-omics integration. Linear short-chain fatty acids were preserved, whereas branched-chain fatty acids were selectively increased in iRBD, indicating a shift toward proteolytic fermentation. Volatile indole was reduced, while p-cresol and 2-octanone were increased, paralleled at the LC-MS/MS level by attenuation of the tryptophan–indole axis, class-level bile acid depletion, and increased acylcarnitines. The microbiome was depleted of Blautia and Faecalibacterium and enriched in Oscillospirales. Integration resolved a coherent host-microbe signature that discriminated iRBD patients from controls within this discovery cohort (84.8% cross-validated accuracy). These cross-sectional findings characterize candidate fecal signatures associated with iRBD; given the exploratory design and the limited sample size, they are hypothesis-generating, and their value for predicting phenoconversion remains to be established in prospective studies.
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BibTeX
@article{ascari2026exploratory,
title = {{Exploratory Metabolomic and Metagenomic Profiling of Fecal Samples in Isolated REM Sleep Behavior Disorder}},
author = {Fabio Ascari and Luca Baldelli and Daniel Scicchitano and Camilla Pellegrini and Francesco Ravaioli and Sara De Fanti and Erika Esposito and Emanuele Porru and Felice Di Laudo and Raffaele Lodi and Maria Giulia Bacalini and Marco Candela and Federica Provini and Jessica Fiori and Nicolò Interino},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101456},
url = {https://www.mdpi.com/2218-273X/16/10/1456},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exploratory Metabolomic and Metagenomic Profiling of Fecal Samples in Isolated REM Sleep Behavior Disorder
AU - Fabio Ascari
AU - Luca Baldelli
AU - Daniel Scicchitano
AU - Camilla Pellegrini
AU - Francesco Ravaioli
AU - Sara De Fanti
AU - Erika Esposito
AU - Emanuele Porru
AU - Felice Di Laudo
AU - Raffaele Lodi
AU - Maria Giulia Bacalini
AU - Marco Candela
AU - Federica Provini
AU - Jessica Fiori
AU - Nicolò Interino
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101456
UR - https://www.mdpi.com/2218-273X/16/10/1456
AB - Isolated REM sleep behavior disorder (iRBD) is among the most reliable prodromal markers of α-synucleinopathies. Under the body-first (gut-first) model of α-synuclein pathology, in which pathology may originate in the enteric nervous system and ascend to the brain, the gut is a biologically plausible compartment in which early and accessible molecular alterations might be detectable; however, the fecal metabolome remains poorly investigated in this population. In this exploratory, cross-sectional study of 21 iRBD patients and 15 healthy controls, we characterized fecal samples through an integrated multi-omics framework. The fecal metabolome was profiled on two complementary mass spectrometry platforms: HS-SPME GC-EI-high-resolution MS, used for both untargeted volatilomics and targeted quantification of linear and branched short-chain fatty acids, and untargeted LC-MS/MS for the non-volatile fraction. Gut microbial community composition was characterized on the same material by 16S rRNA gene sequencing, and the metabolomic and microbial layers were combined by DIABLO multi-omics integration. Linear short-chain fatty acids were preserved, whereas branched-chain fatty acids were selectively increased in iRBD, indicating a shift toward proteolytic fermentation. Volatile indole was reduced, while p-cresol and 2-octanone were increased, paralleled at the LC-MS/MS level by attenuation of the tryptophan–indole axis, class-level bile acid depletion, and increased acylcarnitines. The microbiome was depleted of Blautia and Faecalibacterium and enriched in Oscillospirales. Integration resolved a coherent host-microbe signature that discriminated iRBD patients from controls within this discovery cohort (84.8% cross-validated accuracy). These cross-sectional findings characterize candidate fecal signatures associated with iRBD; given the exploratory design and the limited sample size, they are hypothesis-generating, and their value for predicting phenoconversion remains to be established in prospective studies.
SN - 2218-273X
ER -