Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition in which the gut microbiome (GM) plays a central role. However, taxonomic associations derived from 16S ribosomal RNA (rRNA) gene studies have yielded inconsistent results, likely due to limite...

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Autores: Medina Méndez, Juan Manuel|||0000-0002-3548-7491, Iruzubieta Coz, Paula, Fernandez López, Raúl, Crespo, Javier, Cruz, Fernando de la|||0000-0003-4758-6857
Tipo de recurso: artículo
Fecha de publicación:2026
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:dnet:ucreareposit::f34b99eb3484e8c461eaa07477a53629
Acceso en línea:https://hdl.handle.net/10902/40212
Access Level:acceso abierto
Palabra clave:MASLD
Gut microbiome
Metagenomics
Metabolic genes
Metabolites
Functional profiling
Plasmids
Accessory genoma
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spelling Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomesMedina Méndez, Juan Manuel|||0000-0002-3548-7491Iruzubieta Coz, PaulaFernandez López, RaúlCrespo, JavierCruz, Fernando de la|||0000-0003-4758-6857MASLDGut microbiomeMetagenomicsMetabolic genesMetabolitesFunctional profilingPlasmidsAccessory genomaBackground: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition in which the gut microbiome (GM) plays a central role. However, taxonomic associations derived from 16S ribosomal RNA (rRNA) gene studies have yielded inconsistent results, likely due to limited resolution and functional redundancy across taxa. We aimed to identify robust, functionally relevant microbial markers of MASLD using metagenomics and gene-centric profiling. Methods: We analyzed 554 fecal metagenomes from three independent cohorts. Sequencing reads were quality-controlled and taxonomically profiled with multi-marker gene resolution. We quantified the abundance of over 50 target gene families involved in butyrate, methane, trimethylamine (TMA) and short-chain alcohol (SCAs, i.e., ethanol and propanol) metabolism. Their presence was also determined across complete GM genomes and plasmids. Results: Genes involved in butyrate and methane production tended to show lower abundance in MASLD, particularly in cirrhosis, while TMA- and SCA-producing genes were frequently enriched. These functional shifts were accompanied by the depletion of Agathobacter rectalis. Many of the altered genes were highly accessory and encoded on plasmids, suggesting genome-specific functional divergence driven by horizontal gene transfer. Conclusion: MASLD is characterized by a shift toward alcohol- and TMA-producing metabolism, alongside reduced butyrate and methane production -changes driven by accessory and plasmid-borne genes. Gene-centric and mobile genetic element-aware profiling reveals mechanistic microbial contributions to MASLD that remain undetected by taxonomy-based approaches, offering new targets for diagnosis and intervention.This work was funded by grant PID2020-1179236B-100 from the Spanish MINECO, grant PI22/01853 from the Spanish Carlos III Health Institute (ISCIII) and by HORIZON-HLTH-2022-STAYHLTH-02 (agreement No. 101095679) from the European Horizon’s research and innovation programBioMed CentralUniversidad de Cantabria20262026-01-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttps://hdl.handle.net/10902/40212BMC Microbiology, 2026, 26, 70reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:ucreareposit::f34b99eb3484e8c461eaa07477a536292026-06-02T12:39:31Z
dc.title.none.fl_str_mv Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
title Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
spellingShingle Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
Medina Méndez, Juan Manuel|||0000-0002-3548-7491
MASLD
Gut microbiome
Metagenomics
Metabolic genes
Metabolites
Functional profiling
Plasmids
Accessory genoma
title_short Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
title_full Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
title_fullStr Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
title_full_unstemmed Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
title_sort Bacterial metabolic signatures in MASLD predicted through gene-centric studies in stool metagenomes
dc.creator.none.fl_str_mv Medina Méndez, Juan Manuel|||0000-0002-3548-7491
Iruzubieta Coz, Paula
Fernandez López, Raúl
Crespo, Javier
Cruz, Fernando de la|||0000-0003-4758-6857
author Medina Méndez, Juan Manuel|||0000-0002-3548-7491
author_facet Medina Méndez, Juan Manuel|||0000-0002-3548-7491
Iruzubieta Coz, Paula
Fernandez López, Raúl
Crespo, Javier
Cruz, Fernando de la|||0000-0003-4758-6857
author_role author
author2 Iruzubieta Coz, Paula
Fernandez López, Raúl
Crespo, Javier
Cruz, Fernando de la|||0000-0003-4758-6857
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv MASLD
Gut microbiome
Metagenomics
Metabolic genes
Metabolites
Functional profiling
Plasmids
Accessory genoma
topic MASLD
Gut microbiome
Metagenomics
Metabolic genes
Metabolites
Functional profiling
Plasmids
Accessory genoma
description Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial condition in which the gut microbiome (GM) plays a central role. However, taxonomic associations derived from 16S ribosomal RNA (rRNA) gene studies have yielded inconsistent results, likely due to limited resolution and functional redundancy across taxa. We aimed to identify robust, functionally relevant microbial markers of MASLD using metagenomics and gene-centric profiling. Methods: We analyzed 554 fecal metagenomes from three independent cohorts. Sequencing reads were quality-controlled and taxonomically profiled with multi-marker gene resolution. We quantified the abundance of over 50 target gene families involved in butyrate, methane, trimethylamine (TMA) and short-chain alcohol (SCAs, i.e., ethanol and propanol) metabolism. Their presence was also determined across complete GM genomes and plasmids. Results: Genes involved in butyrate and methane production tended to show lower abundance in MASLD, particularly in cirrhosis, while TMA- and SCA-producing genes were frequently enriched. These functional shifts were accompanied by the depletion of Agathobacter rectalis. Many of the altered genes were highly accessory and encoded on plasmids, suggesting genome-specific functional divergence driven by horizontal gene transfer. Conclusion: MASLD is characterized by a shift toward alcohol- and TMA-producing metabolism, alongside reduced butyrate and methane production -changes driven by accessory and plasmid-borne genes. Gene-centric and mobile genetic element-aware profiling reveals mechanistic microbial contributions to MASLD that remain undetected by taxonomy-based approaches, offering new targets for diagnosis and intervention.
publishDate 2026
dc.date.none.fl_str_mv 2026
2026-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10902/40212
url https://hdl.handle.net/10902/40212
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv BMC Microbiology, 2026, 26, 70
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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