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Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America

Methanogenic archaea Methanobrevibacter smithii and Methanosphaera stadtmanae promote mucosal homeostasis and protect from colitis

  • Emily E. Byrd1
  • Benjamin W. Harris2
  • Hongpan Zhang3
  • W. Elise Warren1
  • Sree H. Kolli1
  • Audrey M. Putelo1
  • Mitchell T. McGinty1
  • Michael D. Solga4
  • Melanie R. Rutkowski1
  • Melissa M. Kendall1
4 affiliations
  1. 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908
  2. 2University of Virginia School of Medicine, Charlottesville, VA 22908
  3. 3Department of Genomic Sciences, University of Virginia School of Medicine, Charlottesville, VA 22908
  4. 4Flow Cytometry Core Facility, University of Virginia School of Medicine, Charlottesville, VA 22908
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Abstract

The intestinal microbiota is a critical determinant of mucosal homeostasis, yet the functional contributions of Archaea—which constitute up to 10% of the anaerobic community—remain largely undefined. Here, we provide evidence that the human methanogens Methanobrevibacter smithii (MSm) and Methanosphaera stadtmanae (MSt) promote colonic health. Transcriptomic analysis of germ-free mice reveals that MSm and MSt induce distinct colonic programs important for epithelial integrity. Using gnotobiotic and antibiotic-treated specific-pathogen-free mouse models, we show that MSm and MSt reinforce the epithelial barrier, characterized by increased goblet cell expansion, mucus thickening, and enhanced epithelial regeneration. Furthermore, methanogens expand Foxp3+ regulatory T cell (Treg) populations without inducing pro-inflammatory TH17 responses. Notably, MSm and MSt protect against dextran sodium sulfate-induced colitis. While MSt-mediated protection requires adaptive immunity, MSm retains partial efficacy in lymphocyte-deficient mice, revealing nonredundant protective mechanisms. These findings indicate that methanogenic archaea promote mucosal integrity during host association and suggest that methanogens may hold therapeutic potential for inflammatory bowel disease, though translation to human disease remains to be established.

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Cite

BibTeXRIS
BibTeX
@article{byrd2026methanogenic,
  title = {{Methanogenic archaea Methanobrevibacter smithii and Methanosphaera stadtmanae promote mucosal homeostasis and protect from colitis}},
  author = {Emily E. Byrd and Benjamin W. Harris and Hongpan Zhang and W. Elise Warren and Sree H. Kolli and Audrey M. Putelo and Mitchell T. McGinty and Michael D. Solga and Melanie R. Rutkowski and Melissa M. Kendall},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2610622123},
  url = {https://doi.org/10.1073/pnas.2610622123},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Methanogenic archaea Methanobrevibacter smithii and Methanosphaera stadtmanae promote mucosal homeostasis and protect from colitis
AU  - Emily E. Byrd
AU  - Benjamin W. Harris
AU  - Hongpan Zhang
AU  - W. Elise Warren
AU  - Sree H. Kolli
AU  - Audrey M. Putelo
AU  - Mitchell T. McGinty
AU  - Michael D. Solga
AU  - Melanie R. Rutkowski
AU  - Melissa M. Kendall
PY  - 2026
DA  - 2026/10/20
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2610622123
UR  - https://doi.org/10.1073/pnas.2610622123
AB  - The intestinal microbiota is a critical determinant of mucosal homeostasis, yet the functional contributions of Archaea—which constitute up to 10% of the anaerobic community—remain largely undefined. Here, we provide evidence that the human methanogens Methanobrevibacter smithii (MSm) and Methanosphaera stadtmanae (MSt) promote colonic health. Transcriptomic analysis of germ-free mice reveals that MSm and MSt induce distinct colonic programs important for epithelial integrity. Using gnotobiotic and antibiotic-treated specific-pathogen-free mouse models, we show that MSm and MSt reinforce the epithelial barrier, characterized by increased goblet cell expansion, mucus thickening, and enhanced epithelial regeneration. Furthermore, methanogens expand Foxp3+ regulatory T cell (Treg) populations without inducing pro-inflammatory TH17 responses. Notably, MSm and MSt protect against dextran sodium sulfate-induced colitis. While MSt-mediated protection requires adaptive immunity, MSm retains partial efficacy in lymphocyte-deficient mice, revealing nonredundant protective mechanisms. These findings indicate that methanogenic archaea promote mucosal integrity during host association and suggest that methanogens may hold therapeutic potential for inflammatory bowel disease, though translation to human disease remains to be established.
SN  - 0027-8424
SN  - 1091-6490
ER  -