Certain species of Archaea—long thought to be a benign subdomain of commensal microbes—may promote the development of colorectal cancer by feeding bacteria known to play an etiologic role in the disease.
A recent international study headed by researchers at the Medical University Graz, Austria, used advanced metabolic modelling to show that organisms within the Archaea domain—especially Methanobrevibacter Smithii—facilitate the growth of CRC-associated bacteria like Fusobacterium nucleatum.
“For a long time, archaea have been regarded as harmless co-inhabitants of the gut,” explains Christine Moissl-Eichinger, a member of the Med Uni Graz research team. “Our results now demonstrate that, from a functional standpoint, they are far more deeply involved in negative microbial processes than previously assumed.”
“Our experiments demonstrate that archaea can influence the growth of certain bacteria associated with cancer—without themselves being pathogenic.”
—Alexander Manhert, Medical University of Graz
The investigators studied nearly 3,000 metagenomic samples from 19 clinical studies spanning twelve countries. The samples were obtained from people with a wide range of health conditions including CRC, inflammatory bowel disease, type 2 diabetes, and neurological disorders.
Using advanced co-culture and analytic techniques, the researchers were able to study metabolites produced by the various gut commensals, as well as the network interactions between various categories of organisms. Further, they could identify microbial ecosystem patterns associated with specific diseases.
A very consistent finding was the increased prevalence of the archaeon M. smithii in patients with colorectal carcinoma, to a much higher degree than seen in normal subjects or those with other conditions.
Indirect Effects
M. smithii is able to take hydrogen and carbon dioxide byproducts from other gut bacteria, and turn them into methane. This, in turn, promotes the normal bacterial fermentation processes of other gut bacteria, and generally there’s nothing harmful about it. “This type of metabolic cooperation is a natural component of the gut ecosystem,” explains co-author Alexander Mahnert.
Lead author Rokhsareh Mohammadzadeh underscores that archaea turn out to be major contributors to the chemical and microbial diversity of the gut environment, and researchers are just beginning to understand the role these curious organisms play.
But because this metabolic cooperation is essentially a neutral process, there’s always the possibility that archaeons like M. smithii will be feeding unfriendly or even pathogenic organisms, as well as the benign commensals.
“Our experiments demonstrate that archaea can influence the growth of certain bacteria associated with cancer—without themselves being pathogenic,” Mahnert explained.
One such cancer-associated organism is F. nucleatum, which has been identified in higher quantities in colon tumor tissue, compared with colon tissue from healthy people. A 2013 animal study published by Harvard researcher Aleksander Kostic and colleagues suggests that F. nucleatum creates a pro-inflammatory enviroment in colon tissue, and may have a carcinogenic effect by selectively recruiting tumor-infiltrating myeloid cells.
The strong mutualistic relationship between M. smithii and F. nucleatum that the Graz team observed in tissue samples from CRC patients, suggests that the former is facilitating the growth of the latter, and thus indirectly contributing to the carcinogenic process.
A Unique Domain
Though archaea share many morphological traits with bacteria, they have unique structural and metabolic traits that make them distinct from both eukaryotes and prokaryotes.
Many genera within the archaea domain have cell membranes comprised of ether-linked lipids—a feature never seen among eukaryotic or prokaryotic bacteria. Some have a structure called an archaellum, which is functionally similar but morphologically distinct from bacterial flagella. One of the most important features is that many archaea produce methane. It is this factor that makes them key players in human and animal gut microbiomes.
Archaea are found throughout the natural world, and some are able to thrive in extreme environments like volcanic hot springs. In the human microbiome, archaea are found in the mouth, the gut, and on the skin. Commensal archaea are able to utilize a wider range of energy sources than eukaryotic cells. This includes sugars, ammonia, metal ions and hydrogen gas.
Master Mutualists
Archaea are master mutualists, in part because of their ability to generate methane. In forming mutualistic associations with healthy commensal bacteria, they play key roles in regulating microbial diversity and stabilizing the gut microbiome. Because of this, they facilitate digestion for their animal hosts.
One of the most spectacular examples of archaeal mutualism is in the relationship between methanogenic archaea and certain protozoans within the digestive tracts of termites. These protozoa are able to break down plant cellulose, which provides energy for the termite. But the process generates a lot of hydrogen waste, which attenuates energy production. The archaea convert the hydrogen to methane, thus maximizing protozoal energy production.
An Under-estimated Component
In the human gut, “Archaea are integral components of microbial networks and must be given greater consideration in the future when interpreting microbiome data,” the Graz researchers write. They believe until recently, the archaea have been an under-estimated and under-studied component of the gut microbiome.
This new research indicates that “changes in archaeal communities are disease-specific and highly variable.” The strong mutualistic relationship between M. smithii, and F. nucleatum and some other cancer-related bacteria raises important questions and suggests potential for new directions in cancer research.
That said, the Graz team stresses that their study “provides no evidence that archaea cause cancer,” and it should not be misconstrued as suggesting a direct causal link. “Rather, the data suggest that the microbial network within the gut changes over the course of the disease—and that archaea are part of these adaptations.”
This, they say, opens up new perspectives on the etiology of CRC, and possibly other types of cancer.
“Our goal is to understand the microbiome as a dynamic system,” Dr. Moissl-Eichinger says. “Only in this way can we ultimately determine which microbial constellations contribute to health—and which undergo changes during the course of a disease.”
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