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Small genetic element provides big insights into individual and community health

Plasmids are small segments of DNA that replicate on their own, without assistance from the host chromosome.They often carry genes that are beneficial to their hosts and have been studied extensively for their involvement with evolution and bacterial genetics, particularly, the dissemination of genes for antibiotic resistance.

However, there is a large group of plasmids that don’t seem to have any genetic function. These “cryptic plasmids” are small and often difficult to study because they have no observable effect on the host cell.

A research team decided to conduct an in-depth exploration of one such cryptic plasmid, pBI143, one of more than 68,000 plasmids found in the human gut and which 90 percent of people in the industrialized world possess (microbiomes of individuals living in industrialized countries typically differ than those of people living in less industrialized areas).

The team’s findings, recently published in Cell, were eye-opening. Turns out pBI143, which was discovered decades ago, is much better at detecting human fecal contamination in water samples than the most current state-of-the-art markers, a crucial finding considering that human fecal pollution is a major global health problem.

Amy Willis
UW Associate Professor of Biostatistics Amy Willis' research group examined the copy number of the cystic plasmid pBI143 relative to its host across gut microbiomes, and compared these across people with and without irritable bowel disease (IBD). 

And the surprises didn’t stop there; pBI143 levels can be used to measure stress on the human gut, a characteristic of inflammatory bowel disease (IBD).

“It surprised me that, despite all of the studies into the human gut microbiome, we knew almost nothing about the ecology and evolution of pBI143, especially given that mobile genetic elements can convey dangerous functions such as antibiotic resistance,” said Amy Willis, an associate professor of biostatistics at the University of Washington School of Public Health and one of the study’s co-authors.

For the study, Willis and collaborators examined the copy number of pBI143 relative to its host across gut microbiomes, and compared these across people with and without IBD. Willis said that executing the analysis wasn't complicated, but carefully designing the analysis plan was critical.

“This analysis required careful consideration of the limitations of shotgun sequencing data, because it's easy to be misled by artifacts of sampling that actually have little to do with true biological signals about abundance. This is what my research group — the StatDivLab — studies, which is why Dr. A. Murat Eren and Dr. Emily Fogarty [the study’s lead and first authors] involved me,” said Willis, who was amazed that the number of copies of the plasmid relative to its host was significantly higher in people with high gut inflammation, and that the signal was so strong.

“By now we have a fairly good understanding of what bacteria, archaea and fungi live in the human gut, but this paper makes it very clear that we have almost no idea about other genetic elements are in the human gut... even when they are very, very common! After so many years, we are still learning things that live in our bodies,” said Willis.