Archaea have vast regulatory effects on the microbiome


All multicellular organisms harbor an unimaginably large number of microorganisms in and on their bodies. The microbiome, i.e. the totality of these microbes, forms a functional, symbiotic unit with the host organism.

From supporting nutrient uptake to protecting against pathogens, microorganisms perform vital tasks for the host. On the contrary, disturbances of the microbiome can cause various serious diseases, including inflammatory bowel disease.

In recent years, scientists have presented a large number of microbiome studies. Therein, they investigated connections between the composition and function of the body’s microbiome and the development of disease. Most of this work has focused primarily on bacteria, whose various species dominate the microbiome in terms of numbers.

One particular group of microorganisms has received little attention so far: the archaea. Although they make on average “only” 1.2 percent of the total microbiome in the intestine, archaea have vast regulatory effects on the microbiome, as shown in earlier studies.

An international research team with the participation of Kiel University, the Medical University of Graz, Austria, and other international partner institutions from the UK and France, has now presented a characterisation of the hitherto insufficiently profiled “archaeome” of the human intestine on the basis of extensive genome data from large cohorts from various global locations.

With this inventory, the researchers led by Professor Ruth Schmitz-Streit from Kiel University’s Microbiology and her colleague from Graz, Professor Christine Moissl-Eichinger, want to expand knowledge about this clade of microorganisms. In the process, they were able to identify so far unknown archaeal species. The scientists recently published their research results in the scientific journal Nature Microbiology.

Far more diverse than previously known

The new analysis provides the first comprehensive description of the human archaeome. The research team used data sources from numerous existing microbiome studies, each of which includes the complete genetic information of the individual intestinal microbial colonization of the participating test persons.

“First of all, we were able to establish that the human archaeome is far more diverse than was previously known and that it features a core composition of roughly the same species in most people regardless of external factors such as geography, gender or age,” emphasizes Dr. Cynthia Chibani, a research associate in Schmitz-Streit’s working group. “In addition to the numerous newly discovered species, we were also able to identify previously unknown types of viruses that can infect archaea,” Chibani continues.

In addition to just compiling the species, the research team also looked for connections with already known patterns in the genetic information of the archaea. To do this, they examined more than 28,000 so-called protein clusters, which indicate significant correlations between the archaeal colonization in the intestine and socio-demographic characteristics of the human hosts.

“The occurrence of certain species and the proteins they produce can potentially be used to draw conclusions about age groups or lifestyles, for example,” explains Chibani, who carried out the bioinformatic analyses together with shared first author Dr. Alexander Mahnert. “At present, however, such meaningful correlations cannot yet be reliably read with regard to possible archaeome-associated disease patterns,” Chibani continues.

One other important finding was the split of the previously known species Methanobrevibacter smithii into two species-level clades based on genomic information. M. smithii and its new “sister” Methanobrevibacter intestini are highly prevalent in numerous persons. The interplay of those two closely related species and the relevance for human health remains to be deciphered.

So far, the link of these methane-forming archaea with disease, such as colon cancer or inflammatory bowel disease has not clearly been resolved, probably due to the missed species-resolution to date. For sure, such methanogens are able to support the activity of pathogenic bacteria, for example by consuming inhibitory metabolic products. The research work now published expands the understanding of the human archaeome and provides an extensive genome and protein catalog for future analyses.

First steps for functional characterisation of the archaeome

Overall, science is only at the beginning in identifying the full diversity of archaea. “The protein catalog of archaea consisting of 1.8 million proteins can be used in the future as a unique source for developing novel research questions,” emphasizes Schmitz-Streit, who, together with colleagues in Graz, is particularly active in advancing archaeal research.

“These future approaches include, for example, studying the physiology and metabolism of the newly identified archaea or the nature of their communication with the human host,” Schmitz-Streit continues. In order to be able to study the functional aspects of the archaeome in the future, the development of new analytical methods is necessary, as these are currently mainly tailored to bacterial species, as well as targeted cultivation of archaea from the human gut.

“Overall, our work contributes significantly to the understanding of the human microbiome as a complex, multi-layered network of bacteria, archaea, fungi and viruses,” Moissl-Eichinger summarizes. On this basis, the researchers hope to decipher the effects of archaea on human physiology and possibly their involvement in disease development step by step in future in-depth work.

The human microbiome is increasingly recognized as a key player in human health1. Although most research has focused on the bacterial component2 and its bacteriophages3,4, and to some extent unicellular eukaryotes (including fungi) and their viruses, the archaea have been largely overlooked, mainly due to methodological reasons5,6,7,8,9.

Archaea are prokaryotes, like bacteria, but are different in cell structure, metabolism and molecular machinery (summarized in ref. 9). Archaea linked with the human gut microbiome are mainly methanogenic archaea, of which only a few have been isolated. Methanogenesis is a unique metabolic process, during which C1 or C2 carbon compounds, such as CO2, CO, formate, acetate or methyl compounds serve as substrates for the formation of methane. It is a highly syntrophic metabolism, as end-products of bacterial fermentation are consumed.

The most prevalent archaea in the human gut are Methanobacteriales and Methanomassiliicoccales. Methanobacteriales are mainly represented by Methanobrevibacter smithii (prevalence of up to 97.5%) and Methanosphaera stadtmanae (prevalence of up to 23%10,11,12). Methanomassiliicoccales have only recently been discovered and identified in the human gut, with Methanomassiliicoccus luminyensis13, Candidatus Methanomassiliicoccus intestinalis14, Ca. Methanomethylophilus alvus15, and the strains Mx02, Mx03 and Mx06, being most prevalent (up to 80%16). Numerous additional archaeal signatures have been retrieved by amplicon- and metagenome-based microbiome analyses, indicating the presence of a complex archaeome in the human gastrointestinal tract (GIT)8,17,18.

Some archaea carry adaptive traits for colonization of the human gut environment, such as bile salt hydrolases19 and adhesin-like proteins16,20. Besides, archaea can degrade deleterious bacterial metabolites such as trimethylamine (TMA)16,21,22 and can induce specific host immune responses7,23,24. Overall, the role of the human archaeome, particularly in health and disease6,9, still needs to be explored, with the most puzzling question, whether archaeal pathogens do exist, as an intrinsically pathogenic capacity of archaea has never been identified.

Based on the recent activities to generate and collect thousands of metagenome-assembled genomes (MAGs) from metagenomic datasets of human GIT2,25,26,27, a treasure of information was produced. In the present study, we present a public catalogue composed of 1,167 archaeal genomes and 28,581 protein clusters derived from the human gastrointestinal archaeal community. Leveraging this comprehensive sequence collection, we gain previously undescribed insights into the abundance, distribution, composition and function of the human archaeome.

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The human microbiome consists of bacteria, archaea, eukaryotes, and viruses. The overwhelming majority of microbiome studies is bacteria-centric, but in recent years, the number of human microbiome studies targeting eukaryotes (e.g., fungi), and viruses has increased (Seed, 2014; Zou et al., 2016; Halwachs et al., 2017).

However, most microbiome studies still overlook the human archaeome (Eisenstein, 2018; Moissl-Eichinger et al., 2018). A few of the underlying reasons for the under-representation of archaea in microbiome studies are:

(i) primer mismatches of the “universal primers” (Raymann et al., 2017);

(ii) low abundance of the archaeal DNA in the studied samples (Mahnert et al., 2018);

(iii) improper DNA extraction methods (Ghavami et al., 2015); and

(iv) the incompleteness of the 16S rRNA gene reference databases due to missing isolates, especially for the DPANN superphylum (Castelle et al., 2015; Mahnert et al., 2018).

Moreover, the clinical interest on archaea has been comparatively insignificant, as no archaeal pathogens have been identified (Gill et al., 2006).

Nevertheless, archaea (e.g., methanogens) are among the commensal microorganisms inhabiting the human body. Such archaea are regularly detected in the oral cavity and the gastrointestinal tract (Horz and Conrads, 2011; Gaci et al., 2014; Chaudhary et al., 2015; Nkamga et al., 2017). In the latter, they can even outnumber the most abundant bacterial species by as much as 14%, as revealed in a shotgun-based metagenomic analysis of gut samples of 96 healthy Russian adults (Tyakht et al., 2013).

Most studies of archaea in humans use either cultivation or qPCR-based detection methods (Dridi et al., 2009, 2012; Borrel et al., 2017; Grine et al., 2017; Koskinen et al., 2017; van de Pol et al., 2017; Wampach et al., 2017). Only a few 16S rRNA-based archaea-centric studies are available (Mihajlovski et al., 2010; Hoffmann et al., 2013; Koskinen et al., 2017; Moissl-Eichinger et al., 2017). These studies show that archaea are also present in the human respiratory tract (Koskinen et al., 2017) and on human skin in considerable amounts (Probst et al., 2013; Moissl-Eichinger et al., 2017).

It has also been shown that archaea reveal body site-specific patterns as do human-associated bacteria (Koskinen et al., 2017). For example, the gastrointestinal tract is dominated by methanogens, the skin by Thaumarchaeota, the lungs by Woesearchaeota, and the nasal archaeal communities are composed of a mixture of mainly methanogens and Thaumarchaeota. Together, these data demonstrate a substantial presence of archaea in some, or even all, human tissues.

As a logic progression from our previous studies, we have begun to optimize the detection of archaea commensals in humans. Specifically, we tested, in silico and experimentally, 27 different 16S rRNA gene-targeting primer pair combinations suitable for NGS amplicon sequencing with the goal of detecting the archaeal diversity in samples from different body sites, including: respiratory tract (i.e., nasal samples), digestive tract (i.e., oral biofilms, appendix biopsy specimens, and stool samples), and skin.

reference link :

More information: Cynthia Maria Chibani et al, A catalogue of 1,167 genomes from the human gut archaeome, Nature Microbiology (2021). DOI: 10.1038/s41564-021-01020-9


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