Through three complementary publications, this work focuses on the distribution, function, and disease associations of human-associated archaea. Chapter 1 provides a comprehensive overview of archaeal diversity and biology across the human body. It summarizes their unique metabolic features, ecological interactions, and relevance to health and disease. The review also highlights major knowledge gaps in archaeal research, emphasizing the need for archaeome-inclusive approaches in microbiome studies to better understand microbe–microbe and microbe–host interactions. Chapter 2 explores age-related archaeal dynamics in the human gut across three age groups (young adults, older adults, and centenarians). The study reveals significant compositional shifts of methanogenic archaea during aging. While overall archaeal diversity declines with age, centenarians display a community structure similar to that of younger individuals, enriched in Methanobrevibacter smithii and characterized by strong archaeal–bacterial network connectivity. Functionally, high methanogen phenotypes are associated with enhanced short-chain fatty acid metabolism through alternative butyrate pathways, suggesting that archaea may contribute to metabolic resilience and microbiome stability in extreme aging. Chapter 3 investigates the disease-specific role of archaea through a large-scale meta-analysis of shotgun metagenomes across multiple disorders, including colorectal cancer (CRC). The study identifies a consistent enrichment of M. smithii in CRC. Integrative metabolic modeling, co-culture experiments, and metabolomic profiling show that M. smithii engages in metabolic interactions with CRC-associated bacteria such as Fusobacterium nucleatum. Through cross-feeding of metabolites including succinate, amino acids, and polyamine precursors, M. smithii influences bacterial metabolism and promotes the formation of a metabolically active, cancer-associated microbiome. This work provides the first mechanistic evidence linking archaeal activity to colorectal carcinogenesis and redefines archaea as active metabolic regulators rather than passive microbial residents.
The human archaeome and its implications for human health
Mohammadzadeh, R. (Author). 2026
Student thesis: Doctoral thesis