Contributions of Human-Associated Archaeal Metabolites to Tumor Microenvironment and Carcinogenesis

ABSTRACT There is increasing awareness that archaea are interrelated with human diseases (including cancer). Archaea utilize unique metabolic pathways to produce a variety of metabolites that serve as a direct link to host-microbe interactions. However, knowledge on the diversity of human-associated archaea is still extremely limited, and less is known about the pathological effects of their metabolites to the tumor microenvironment and carcinogenesis. In the present study, we performed a large-scale analysis of archaea and their cancer-related metabolites across different body sites using >44,000 contigs with length >1,000 bp. Taxonomy annotation revealed that the occurrence and diversity of archaea are higher in two body sites, the gut and the oral cavity. Unlike other human-associated microbes, the nonmetric multidimensional scaling (NMDS) and permutational multivariate analysis of variance (PERMANOVA) analyses have shown no difference of archaeal compositions between Easterners and Westerners. Likewise, protein annotation suggests that genes encoding cancer-related metabolites (e.g., short-chain fatty acids and polyamines) are more prevalent and diverse in gut and oral samples. Archaea carrying these metabolites are restricted to Euryarchaeota and the TACK superphylum (Thaumarchaeota, Aigarchaeota, Crenarchaeota, and Korarchaeota), especially methanogenic archaea, such as Methanobacteria. IMPORTANCE More evidence suggests that archaea are associated with human disease, including cancer. Here, we present the first framework of the diversity and distribution of human-associated archaea across human body sites, such as gut and oral cavity, using long contigs. Furthermore, we unveiled the potential archaeal metabolites linking to different lineages that might influence the tumor microenvironment and carcinogenesis. These results could open a new door to the guidance of diagnosing cancer and developing new treatment strategies.