A widespread hydrogenase supports fermentative growth of gut bacteria in healthy people
Disruption of hydrogen (H<sub>2</sub>) cycling in the gut is linked to gastrointestinal disorders, infections and cancers. However, the mechanisms and microorganisms controlling H<sub>2</sub> production in the gut remain unresolved. Here we show that gut H<sub>2</sub> 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 H<sub>2</sub> 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 H<sub>2</sub> cycling in the healthy human gut.
Authors
- Rachael J. Lappan (ORCID: https://orcid.org/0000-0002-3543-8243)
- Samuel C. Forster (ORCID: https://orcid.org/0000-0003-4144-2537)
- Ping Huang (ORCID: https://orcid.org/0000-0002-7676-6905)
- Henrik Land (ORCID: https://orcid.org/0000-0003-3073-5641)
- Gustav Berggren (ORCID: https://orcid.org/0000-0002-6717-6612)
- Duncan J. Kountz (ORCID: https://orcid.org/0000-0002-7824-0261)
- Remy B. Young (ORCID: https://orcid.org/0000-0002-1458-2895)
- H. Rex Gaskins (ORCID: https://orcid.org/0000-0002-1249-535X)
- Patricia G. Wolf (ORCID: https://orcid.org/0000-0003-4779-7910)
- Jason M. Ridlon (ORCID: https://orcid.org/0000-0001-5813-099X)
- Isaac Cann (ORCID: https://orcid.org/0000-0003-0539-0119)
- Marion Jespersen (ORCID: https://orcid.org/0000-0002-8859-3335)
- Gemma L. D’Adamo
- Eric C. Martens (ORCID: https://orcid.org/0000-0001-6681-2990)
- Caitlin Welsh (ORCID: https://orcid.org/0009-0000-1720-5246)
- Chris Greening (ORCID: https://orcid.org/0000-0001-7616-0594)
- Princess R. Cabotaje (ORCID: https://orcid.org/0000-0002-0500-5981)
- Jodee A. Gould
- Edward Giles (ORCID: https://orcid.org/0000-0003-3295-1575)
- Vanessa R. Marcelino (ORCID: https://orcid.org/0000-0003-1755-0597)
- Thomas D. Watts (ORCID: https://orcid.org/0000-0002-3657-8790)
- Dena Lyras (ORCID: https://orcid.org/0000-0003-2345-9271)
- Emily L. Gulliver (ORCID: https://orcid.org/0000-0002-1820-6619)
- Gabriel Vasconcelos Pereira (ORCID: https://orcid.org/0000-0001-7937-474X)
- James P. Lingford (ORCID: https://orcid.org/0000-0003-1980-3949)
- Natasha Bong
- Jessica Solari
- Nhu Quynh Doan
- Kaija Walter
- Thilini Koralegedara
Institutions
- Uppsala University (SE)
- Harvard University (US)
- University of Illinois Urbana-Champaign (US)
- The University of Melbourne (AU)
- Purdue University West Lafayette (US)
- University of Michigan (US)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- Hudson Institute of Medical Research (AU)
- Peter Doherty Institute (AU)
- Monash Health (AU)
- Melbourne Genomics Health Alliance (AU)
- Monash University (AU)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1038/s41564-025-02154-w
- Citations
- 3
- Primary Topic
- Metalloenzymes and iron-sulfur proteins
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Australian Government
- Monash University
- Novo Nordisk
- Vetenskapsrådet
- Energimyndigheten
- State Government of Victoria
- Novo Nordisk Fonden
- National Health and Medical Research Council