Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species
Abstract Urolithin A (uroA) is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota. Once absorbed, uroA can trigger mitophagy and aryl hydrocarbon receptor signaling pathways, altering host immune function, mitochondrial health, and intestinal bar...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56266-2 |
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| author | Reilly Pidgeon Sacha Mitchell Michael Shamash Layan Suleiman Lharbi Dridi Corinne F. Maurice Bastien Castagner |
| author_facet | Reilly Pidgeon Sacha Mitchell Michael Shamash Layan Suleiman Lharbi Dridi Corinne F. Maurice Bastien Castagner |
| author_sort | Reilly Pidgeon |
| collection | DOAJ |
| description | Abstract Urolithin A (uroA) is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota. Once absorbed, uroA can trigger mitophagy and aryl hydrocarbon receptor signaling pathways, altering host immune function, mitochondrial health, and intestinal barrier integrity. Most individuals harbor a microbiota capable of uroA production; however, the mechanisms underlying the dehydroxylation of its catechol-containing precursor (uroC) are unknown. Here, we use a combination of untargeted bacterial transcriptomics, proteomics, and comparative genomics to uncover an inducible uroC dehydroxylase (ucd) operon in Enterocloster species. We show that the ucd operon encodes a predicted molybdopterin-dependent enzyme complex that dehydroxylates urolithins at a specific position (9-OH). By interrogating publicly available metagenomics datasets, we observed that uroC-metabolizing Enterocloster species and ucd operon genes are prevalent in human feces. In ex vivo experiments with human fecal samples, only samples actively transcribing ucd could produce uroA, possibly explaining differences in urolithin metabolism between individuals. Collectively, this work identifies Enterocloster species and the ucd operon as important contributors to uroA production and establishes a multi-omics framework to further our mechanistic understanding of polyphenol metabolism by the human gut microbiota. |
| format | Article |
| id | doaj-art-3f6e492c96cd48a79ec1c9195aacd11e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3f6e492c96cd48a79ec1c9195aacd11e2025-01-26T12:42:20ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-025-56266-2Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster speciesReilly Pidgeon0Sacha Mitchell1Michael Shamash2Layan Suleiman3Lharbi Dridi4Corinne F. Maurice5Bastien Castagner6Department of Pharmacology & Therapeutics, McGill UniversityDepartment of Pharmacology & Therapeutics, McGill UniversityDepartment of Microbiology & Immunology, McGill UniversityDepartment of Pharmacology & Therapeutics, McGill UniversityDepartment of Pharmacology & Therapeutics, McGill UniversityDepartment of Microbiology & Immunology, McGill UniversityDepartment of Pharmacology & Therapeutics, McGill UniversityAbstract Urolithin A (uroA) is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota. Once absorbed, uroA can trigger mitophagy and aryl hydrocarbon receptor signaling pathways, altering host immune function, mitochondrial health, and intestinal barrier integrity. Most individuals harbor a microbiota capable of uroA production; however, the mechanisms underlying the dehydroxylation of its catechol-containing precursor (uroC) are unknown. Here, we use a combination of untargeted bacterial transcriptomics, proteomics, and comparative genomics to uncover an inducible uroC dehydroxylase (ucd) operon in Enterocloster species. We show that the ucd operon encodes a predicted molybdopterin-dependent enzyme complex that dehydroxylates urolithins at a specific position (9-OH). By interrogating publicly available metagenomics datasets, we observed that uroC-metabolizing Enterocloster species and ucd operon genes are prevalent in human feces. In ex vivo experiments with human fecal samples, only samples actively transcribing ucd could produce uroA, possibly explaining differences in urolithin metabolism between individuals. Collectively, this work identifies Enterocloster species and the ucd operon as important contributors to uroA production and establishes a multi-omics framework to further our mechanistic understanding of polyphenol metabolism by the human gut microbiota.https://doi.org/10.1038/s41467-025-56266-2 |
| spellingShingle | Reilly Pidgeon Sacha Mitchell Michael Shamash Layan Suleiman Lharbi Dridi Corinne F. Maurice Bastien Castagner Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species Nature Communications |
| title | Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species |
| title_full | Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species |
| title_fullStr | Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species |
| title_full_unstemmed | Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species |
| title_short | Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species |
| title_sort | diet derived urolithin a is produced by a dehydroxylase encoded by human gut enterocloster species |
| url | https://doi.org/10.1038/s41467-025-56266-2 |
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