Archaea Inhabit Our Microbiome, but What Are They Doing There?

Over 1500 bacterial species can cause human disease, as can hundreds of eukaryotic pests, like fungi, protists, and helminth worms. But there is a third domain of life missing from medical literature: archaea.^1,2 This group of microbes, first classified in 1977, was originally mistaken for bacteria due to their similar appearance.³ “Now we have more and more evidence that this domain where the archaea belong is really completely different to bacteria," said Magdalena Kowalewicz-Kulbat, a microbiologist at the University of Lodz.

Photo of Magdalena Kowalewicz-Kulbat. — Magdalena Kowalewicz-Kulbat, a microbiologist at the University of Lodz, studies how halophilic (salt-loving) archaea interact with human cells.
Magdalena Kowalewicz-Kulbat

People often associate archaea with extreme environments like salt lakes, geysers, and hydrothermal events. However, scientists have also found them in oceans, soil, and animal microbiomes.^4,5 Though there is growing evidence that archaea populate the human body, a pathogenic variety has yet to make itself known. With little research devoted to this domain, it has been difficult to determine whether archaea are not pathogenic by nature or whether stealthy, disease-causing members have simply evaded detection.

Detection Difficulties

Despite their classification nearly 50 years ago, archaea still slip under the radar due to microbiologists’ reliance on protocols designed for studying bacteria. This has led to considerable sampling bias.⁶ When researchers cultivate microbes from the body, such as from a stool sample, they routinely use media designed to culture bacteria, which may prevent some archaea from growing. Other archaea may divide too slowly to be picked up by conventional methods. “Some [archaeal] species we grow within weeks. Sometimes it can be even longer,” Kowalewicz-Kulbat said. Sonja-Verena Albers, a microbiologist at the University of Freiberg, added that many archaea are anaerobes, thriving in oxygen-deprived environments like the gut. So, to study them in the lab, scientists must get their hands on special anaerobic chambers.

DNA sequencing can also miss archaea depending on the DNA extraction method used. Most commercial extraction kits include lysozyme, which breaks down peptidoglycan in bacterial cell walls to split open and release DNA; however, the enzyme does not cleave pseudopeptidoglycan in archaeal walls.⁶ Even when archaeal DNA is extracted using other enzymes, bacteria are more abundant gut residents, so their genome sequences tend to dominate metagenomics studies. Adding to the difficulty, scientists have only collected a few referential archaeal sequences so far, reducing the odds that researchers will find similar hits in big datasets and identify new species.⁷

Despite these obstacles, microbiologists have detected archaea in the human microbiome, spanning the gums, gut, lungs, and skin.⁸ Of all the gut archaea, methane-producing microbes called methanogens, found in half of all people and varying in prevalence by population, have garnered the most attention, according to Guillaume Borrel, a microbiologist at the Pasteur Institute. Methane breathalyzer tests can even detect their intestinal presence. “In general, it’s when you have more than 10⁶ methanogens in the gut that you can have sufficient methane produced to detect in breath,” Borrel noted.

Methanogens are not the only human-dwelling archaea. Kowalewicz-Kulbat and other research groups have identified a growing number of halophilic, or salt-loving, gut inhabitants. “I think some researchers didn’t expect that there can be some halophilic archaea, which really require high concentrations of sodium chloride,” she said.

Still, current data suggests gut archaea are not as varied as their bacterial neighbors. “We made a census of the diversity of methanogens in the gut, and we found around 30 species, which is not a lot,” Borrel said. In contrast, there are at least 1,000 bacterial species in the intestines.⁹ Going by abundance, archaea are also minor, contributing to between 0.1 and one percent of the gut microbiome, Borrel added. They only make up one percent of the microbiome on the skin, too, and some studies reveal that they may make skin more acidic and dry.¹⁰

Archaea, in Sickness and in Health?

Though scientists have discovered a few archaeal residents of the microbiome, microbiologists have not classified any as pathogens, suggesting archaea may lack adaptations that cause disease in humans or other animals. There are several potential reasons for this. Given the low diversity of archaeal species, it’s possible that too few archaea have colonized the gut to allow one with pathogenic potential to gain a foothold.⁶ In addition, scientists have yet to find an archaeon with tissue-damaging toxin secretion machinery akin to the ones used by bacteria.¹¹ Archaea rely on metabolites produced by their bacterial neighbors to fuel their growth, so triggering disease in the gut may backfire and cause bacteria-killing inflammation or speed up their removal (e.g. by causing diarrhea).¹² In fact, gut methanogens actively slow gut flow rate by 59 percent in dogs, possibly via interactions between the methane they produce and nerve receptors.¹³ This slower bowel movement may also allow more time for slow-growing archaea to populate the gut.

Some archaea, it seems, promote human health. “We isolated a new species of halophilic archaea in a Polish salt mine,” Kowalewicz-Kulbat said. Given that people often swim in the nearby salt lakes, she reasoned that this archaeon, Halorhabdus rudnickae, may enter the body, where it could react with immune cells. She also wondered if other distantly-related halophilic species, such as Natrinema salaciae, could do the same. To test this, she mixed each of the two species with human dendritic cells and T cells in vitro. They found, for the first time, that both of the halophilic archaea could trigger adaptive immunity, suggesting it could be a general property of the salt-loving species.¹⁴ By primarily switching on anti-inflammatory pathways, halophilic species might tune immune cells to alleviate symptoms of inflammation, Kowalewicz-Kulbat suggested. Future in vivo studies could further explore the impact of archaea on immunity.

Methanogens may also prove beneficial. Some species can break down the host metabolite trimethylamine into methane, preventing trimethylamine oxide from forming in the body—a chemical linked to cardiovascular disease.¹⁵ These findings and others led Borrel to submit a patent for the use of archaea as dietary supplements.

While evidence mounts that some archaea are “good” bugs, it is still possible that “bad” archaea exist but have escaped notice. Scientists have linked some species to disease. For example, they found Methanobrevibacter smithii in the vaginal microbiome of women with vaginosis.¹⁶ Similarly, they spotted Methanobrevibacter oralis in dental pockets affected by periodontitis but not in nearby healthy gums or in affected dental pockets following recovery.¹⁷ Scientists have even linked archaea to abscesses of the brain and muscle, inflammatory bowel disease, and pneumonia, too.⁶ In these cases, the archaea are probably not the primary culprit behind each condition, but they may play a contributing role. For example, they may promote the proliferation of bacterial partners-in-crime that directly cause symptoms. However, proving a causal link between archaea and disease has been tricky because of a lack of experimental protocols and tools for working with this domain of life.

Towards a Toolkit for Archaea

To study how a bacterium causes a disease, microbiologists manipulate their genetics to remove or enhance virulence factors. Studying archaeal bandits would require the same treatment, as scientists still don't know which of their genes may play a role in disease. “Many of the genes that are popping up are hypotheticals—we don’t know their functions,” Albers explained. “In the end, somebody has to do the experiment and find out what that protein is actually doing.” However, Borrel said, “There is no genetic model of gut archaea. There are some genetically tractable models of methanogens, but not the ones that are in the gut.”

Image of Sonja-Verena Albers. — Sonja-Verena Albers, a microbiologist at the University of Freiburg, researches cellular processes in archaea, such as motility.
Marleen van Wolferen, University of Freiburg

Gene editing in archaea would require a molecular toolkit that microbiologists have yet to develop.¹⁸ “You have to find an antibiotic or selection marker that works. You have to find plasmids. It’s much easier in bacteria nowadays, just because there’s more material available,” Albers said. Microbiologists would also need to inoculate animals with archaea to see if they contribute to disease. However, Borrel said, “There is no well-established murine model which could help to see what their impact could be in vivo.”

Archaea research has fallen behind that of bacteria and eukaryotes by three decades, said Albers. She and other microbiologists are still trying to understand the basic cell biology of these microbes. Still, research teams around the world are developing experimental procedures to gain mechanistic insight into archaea. In 2023, researchers identified a plasmid that easily spreads between diverse archaeal species, facilitating gene-editing efforts.¹⁹ “Most of the archaea have CRISPR systems that you can use to internally make mutants,” Albers noted, and, indeed, researchers in 2024 developed CRISPR gene-editing machinery to manipulate methanogens.²⁰

As scientists develop the tools to study these microbes, we may soon understand several facets of their relationship with humans. “Is there any direct interaction with human cells, like epithelial cells of the gut?” Albers wondered. Kowalewicz-Kulbat added that the field still doesn’t know whether innate immune cells detect archaeal components, such as lipids or proteins in their membranes and cell walls. Further findings will hopefully provide more insight into the elusive relationship between this domain of life and the human body.