A widespread hydrogenase supports fermentative growth of gut bacteria in healthy people
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Date
2025
Authors
Welsh, C.
Cabotaje, P.R.
Marcelino, V.R.
Watts, T.D.
Kountz, D.J.
Jespersen, M.
Gould, J.A.
Doan, N.Q.
Lingford, J.P.
Koralegedara, T.
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Journal article
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Nature Microbiology, 2025; 10(11):2686-2701
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Caitlin Welsh, Princess R. Cabotaje, Vanessa R. Marcelino, Thomas D. Watts, Duncan J. Kountz, Marion Jespersen, Jodee A. Gould, Nhu Quynh Doan, James P. Lingford, Thilini Koralegedara, Jessica Solari, Gemma L. D'Adamo, Ping Huang, Natasha Bong, Emily L. Gulliver, Remy B. Young, Henrik Land, Kaija Walter, Isaac Cann, Gabriel V. Pereira, Eric C. Martens, Patricia G. Wolf, Jason M. Ridlon, H. Rex Gaskins, Edward M. Giles, Dena Lyras, Rachael Lappan, Gustav Berggren, Samuel C. Forster, Chris Greening
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Abstract
Disruption of hydrogen (H₂) cycling in the gut is linked to gastrointestinal disorders, infections and cancers. However, the mechanisms and microorganisms controlling H₂ production in the gut remain unresolved. Here we show that gut H₂ production is primarily driven by the microbial group B [FeFe]-hydrogenase. Metagenomics and metatranscriptomics of stool and tissue biopsy samples show that hydrogenase-encoding genes are widely present and transcribed in gut bacteria. Assessment of 19 taxonomically diverse gut isolates revealed that the group B [FeFe]-hydrogenases produce large amounts of H₂ gas and support fermentative growth of Bacteroidetes and Firmicutes. Further biochemical and spectroscopic characterization of purified enzymes show that they are catalytically active, bind a di-iron active site and reoxidize ferredoxin derived from the pyruvate:ferredoxin oxidoreductase reaction. Group B hydrogenase-encoding genes are significantly depleted in favour of other fermentative hydrogenases in patients with Crohn’s disease. Finally, metabolically flexible respiratory bacteria may be the dominant hydrogenotrophs in the gut, rather than acetogens, methanogens and sulfate reducers. These results uncover the enzymes and microorganisms controlling H₂ cycling in the healthy human gut.
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.