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

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.