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

Archaea, one of the three domains of life, are increasingly recognized as consistent, though often underappreciated, members of the human microbiome, yet their roles in health and disease remain poorly understood. Unlike bacteria, no archaeal species have been conclusively identified as primary mammalian pathogens, but their widespread presence across diverse body sites suggests potential indirect contributions to host physiology and pathology. Current evidence is synthesized on archaeal diversity and habitat specificity across multiple human-associated sites, encompassing the gastrointestinal, aerodigestive, and urogenital tracts as well as the skin. Methanogens dominate the lower gastrointestinal tract (LGT), where they influence fermentation dynamics and methane production, while members of the class Nitrososphaeria are prevalent on the skin and upper aerodigestive tract (UAT), reflecting ecological specialization. Variability in archaeal composition across niches highlights possible links to disease processes: methanogens have been associated with irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), obesity, and colorectal cancer (CRC); 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 alteration of host-microbiome network dynamics. This review explores the emerging concept of the human "archaeome", evaluates current evidence for archaeal involvement in disease, and highlights emerging technologies, such as bacteria-MERFISH and multi-omics profiling, that enable translational applications including microbiome diagnostics, therapeutic targeting, and microbiome engineering.