The Human Archaeome: Commensals, Opportunists, or Emerging Pathogens?

Archaea, one of the three domains of life, are abundant members of the human microbiome yet remain poorly understood in health and disease. Unlike bacteria, no archaeal species have been conclusively identified as primary pathogens in mammals, but their presence across diverse body sites suggests important indirect roles. We examine archaeal distribution across the lower gastrointestinal tract (LGT), upper aerodigestive tract (UAT), urogenital tract (UGT), and skin. Methanogens dominate the LGT, where they influence fermentation dynamics and methane production, while members of Nitrososphaeria are prevalent on the skin and UAT, reflecting ecological specialization. Variability in archaeal composition across niches highlights potential links to disease processes: methanogens have been associated with irritable bowel syndrome, inflammatory bowel disease, obesity, and colorectal cancer, while Methanobrevibacter oralis is enriched in periodontal disease, and archaea have been detected in the lungs of cystic fibrosis patients. Although archaea lack canonical bacterial virulence factors, they may contribute indirectly through metabolic cross-feeding, immune modulation, synergy in polymicrobial infections, and microbiome network effects. This review explores the emerging concept of the human “archaeome,” evaluating current evidence for archaeal involvement in disease and outlining future directions to determine their true clinical significance.