Cryptic plasmid offers insights into gut health

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A component of the human gut flora that has until now been little studied is the focus of a new study. Plasmids are small extrachromosomal genetic elements that are often found in bacterial cells and can influence the way microbes live – but their diversity in natural habitats is poorly understood. An international team led by Prof. Dr. A. Murat Eren of the Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB) reports in the scientific journal cell, a mysterious plasmid, is one of the most abundant genetic elements in the human gut that could potentially serve as a powerful biomarker to identify health hazards such as fecal water pollution or human disorders such as inflammatory bowel disease. According to the team’s analysis, this plasmid is present in the intestines of more than 90 percent of individuals in industrialized countries.

Plasmids are extrachromosomal DNA sequences that are common to cells from all walks of life. Eren describes them as “usually small genetic units that carry extra genes.” They can be exchanged between different bacterial cells and even between different types of bacteria. Replication of plasmids depends on their host cells: but they compensate for this by providing their hosts with in some cases extremely important fitness determinants. For example, some plasmids contain genes that encode antibiotic resistance that help their bacterial hosts survive antibiotics, contributing to one of the world’s most pressing public health problems.

There are other plasmids that, according to research to date, do not contain genes encoding obvious useful functions for their host. “These so-called ‘cryptic plasmids’ are often called genetic parasites. They remain a mystery in microbial ecology because, from an evolutionary point of view, they shouldn’t exist at all,” explains Ehren, a computer scientist and professor of ecosystem data at the University of Oldenburg.

Plasmid identification has so far been a difficult endeavor. For some time now, scientists have been able to extract genetic material directly from environmental samples and, for example, analyze the entire microbial community in the human gut without having to culture individual bacterial organisms. However, the ability to confidently distinguish what is a plasmid among this conglomeration of genetic material called the metagenome presents a significant challenge.

To solve this problem, Ehren and his colleagues developed a new machine learning approach. As the team reported in a paper recently published in the scientific journal Natural Microbiologyusing this approach, they identified over 68,000 plasmids in the human gut flora and also found that a particular cryptic plasmid called pBI143 was particularly abundant in their data set.

One of the most numerous genetic units in the human intestine

In the study published in cell, the research team took a closer look at this plasmid, which consists of only two genes, which rather surprisingly only serves its own replication and mobilization in bacterial cells with no other clear benefit. To better understand the ecology of pBI143, the team analyzed 60,000 human and 40,000 environmental metagenomes generated from different habitats. “We found that pBI143 has a list of very interesting features,” explains Ehren. The team found that more than 90 percent of people in industrialized countries carry the plasmid and that, on average, it is one of the most abundant genetic entities in the human gut “On average, it is more than ten times more abundant than a previously thought viral genome , that it is the most abundant genetic extrachromosomal element in the human gut,” says the researcher.

Further analyzes revealed that the plasmid is found almost exclusively in the human gut, but is virtually absent from datasets from other environments such as oceans, soils, plants, and animal digestive organs and their feces. The only other samples in which the researchers were able to find the characteristic gene sequence for these plasmids were in samples from environments that are influenced by humans, such as sewage, hospital surfaces and laboratory rats.

Because of its large number, distribution in humans and its persistence in human populations, the research team hypothesized that pBI143 could, for example, be used as a biomarker in fecal contamination testing. “In fact, we were able to show that this plasmid is a more sensitive marker for detecting fecal contamination in drinking water compared to state-of-the-art biomarkers based on specific gene sequences of human gut bacteria,” says Ehren.

A non-invasive method to quantify IBD progression

The team also identified another potential application of this prevalent genetic unit in the context of human disorders such as inflammatory bowel disease (IBD), a medical condition that affects 3 million people in Europe alone. They were able to demonstrate that the relative copy number of this cryptic plasmid increased almost fourfold in the intestines of people suffering from IBD compared to the intestines of healthy individuals, suggesting that changes in plasmid copy number may serve as a non-invasive method to quantify disease progression or severity.

At HIFMB, Ehren’s team is developing new tools at the intersection of computer science and microbiology to identify and characterize naturally occurring plasmids and other mobile genetic elements in ocean-dwelling bacteria. They seek to better understand the ecology and evolution of microbes and the strategies that allow them to respond to ever-changing environments for new biotechnological applications that can alleviate the crises we face.

Reference: Fogarty EC, Schechter MS, Lolans K, et al. The cryptic plasmid is among the most abundant genetic elements in the human gut. cell. 2024; 187 (5): 1206-1222.e16. doi: 10.1016/j.cell.2024.01.039

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