Billions of microorganisms—primarily bacteria, viruses, and fungi—colonize our gut. This complex community is known as the microbiome. When the microbiome is diverse and in balance, it has a positive effect on our health: digestion runs smoothly, and pathogens cannot harm us as easily.

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However, not all microbiomes are the same; they differ from person to person. Yet there are patterns. Studies have shown that in regions of the world such as Africa or Asia, where a more traditional lifestyle still prevails, bacteria of the genus Segatella dominate the human gut microbiome.

“In industrialized countries, representatives of the genus Segatella are also present in the gut, but the microbiome is dominated by bacteria of the genus Bacteroides,” says Prof. Till Strowig, head of the department “Microbial Immune Regulation” at the HZI and last author of the study. “With this study, we wanted to get a little closer to answering the question of why.”

Oxygen tolerance

In their first experiment, the researchers investigated the oxygen tolerance of Segatella copri, likely the most common gut bacterium worldwide. Whether oxygen is present in their habitat or not is crucial for bacteria. There are bacteria that—like us humans—require oxygen for their metabolism. Others, however, do not necessarily need oxygen or do not need it at all, but can tolerate it in small amounts. For some bacteria, oxygen can even be toxic.

“In a healthy gut, there is usually very little oxygen present, and in most areas, none at all. For bacteria that cannot cope with oxygen, or cannot cope with it very well, this is therefore an optimal habitat,” says Dr. Youssef El Mouali, a scientist on Till Strowig’s team and one of the study’s first authors.

For their investigations, the researchers used various bacterial strains of the species Segatella copri as well as the bacterial model organism Bacteroides thetaiotaomicron for comparison.

“Over a period of 30 minutes, we exposed the bacteria to a defined oxygen concentration,” explains Dr. Caroline Tawk, a scientist in Strowig’s team and also a first author of the study. “It is well known that Bacteroides species can tolerate the presence of oxygen well. In comparison, the survival rate of Segatella copri was 100,000 times lower.”

Mystery strategy

However, even though the oxygen tolerance of Segatella copri was low, the scientists concluded that the bacteria must possess a strategy that helped them survive under the influence of oxygen. But what was it?

To find out, they exposed Segatella copri to oxygen for a few minutes in subsequent experiments and then performed a so-called transcriptome analysis. This allows researchers to determine which genes are active at a given time.

“In Segatella copri, we identified the known transcription regulator PerR, which controls a genetic network that is crucial for the bacterial oxygen response,” says Youssef El Mouali. “In a mouse model, we were also able to show that Segatella copri cannot colonize the gut without the presence of PerR. PerR is therefore crucial for this bacterium to successfully colonize the gut.”

Surviving oxygen stress

To investigate whether Segatella copri might possess additional regulatory mechanisms to survive oxygen stress, the researchers combed through databases and examined several hundred genomes of different strains of Segatella copri. They specifically searched for genetic traces of the transcription regulator OxyR, which regulates the oxygen response in bacteria of the genus Bacteroides, among others.

And indeed, they found some strains of Segatella copri that possessed OxyR. The strains the researchers had used for the experiment to investigate oxygen tolerance, however, did not possess OxyR. The researchers therefore repeated the experiment specifically with strains containing OxyR to test whether these could handle oxygen better.

And indeed: The strains of Segatella copri with OxyR exhibited a hundred to a thousand times higher oxygen tolerance than strains without OxyR. But how is it that some strains possess OxyR and others do not?

“Our investigations suggest that a so-called horizontal gene transfer likely took place several thousand years ago. In this process, bacteria—sometimes even of different species—exchange genes with one another,” explains Till Strowig.

Global spread

In further investigations supported by the team of Nicola Segata at University of Trento, the researchers explored where in the world strains of the gut bacterium Segatella copri with and without OxyR occur in the human microbiome. To do this, they conducted extensive genomic data analyses and found that strains of Segatella copri with OxyR occur primarily in industrialized countries, whereas they are significantly rarer in African and most Asian countries. But why is that?

“We suspect that bacterial strains of Segatella copri with OxyR have a selective advantage in highly industrialized countries,” says Till Strowig. “On the one hand, because disturbances in the gut’s balance occur more frequently here—for example, due to antibiotic use—which can temporarily lead to increased oxygen availability in the gut.

”On the other hand, human-to-human transmission could also be challenging due to higher hygiene standards. Better oxygen tolerance, allowing the bacterium to survive longer periods in the open air until transmission to the next host, could be quite helpful for the exclusively gut-dwelling bacterium Segatella copri.”

Adaptive abilities

With their study, the researchers were able to impressively demonstrate that gut bacteria of the same species can exhibit such decisive genetic differences at the strain level that they lead to entirely different characteristics and adaptive abilities under changing environmental conditions. In future research projects, Till Strowig’s team plans to investigate how intestinal colonization by Segatella copri—depending on the strain, with or without the genetic bonus material from OxyR—affects human health.

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