Research Spotlight: How Microbes in the Human Gut Swap Genetic Traits

Long H. Nguyen, MD, MS, of the Department of Medicine and the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital, is the co-senior author of a paper published in Nature Microbiology, Profiling lateral gene transfer events in the human microbiome using WAAFLE.”

How would you summarize your study for a lay audience?

Our study was focused on the microbial phenomenon known as lateral gene transfer (LGT), also known as horizontal gene transfer (HGT). LGT is nature’s way of allowing bacteria and other organisms to swap genetic traits—such as antibiotic resistance—without waiting for traditional reproduction. As you might imagine, this can significantly impact the health of the microbe itself or even our own health, given how the microbes that make up the human microbiome affect us.

While we suspected that this was occurring rather frequently, to date there had been no widely adopted methods to characterize LGT at scale, so we developed, benchmarked, and validated a computational algorithm (WAAFLE or Workflow to Annotate Assemblies and Find LGT Events) to profile LGT from mixed microbial communities, such as the types associated with humans. We then applied this method to a large set of microbiome samples from healthy individuals. 

What did you find?

We were able to not only quantify these LGT events but also describe what genes were being exchanged. We found interesting functions related to microbial virulence, the destruction of foreign DNA, and other relevant pathways that probably improve the fitness of the microbes involved. We also saw that LGT frequency was influenced by how close together the microbes were in their environment, how similar they were genetically, and how many of the donor microbes were in a community.

Now that we have a more reliable way to quantify and characterize these events, we can better understand why certain microbes become more fit and survive better in certain environments or even how they acquire important genes related to antibiotic resistance.

While there are a number of software-based improvements we would like to make to the next version of WAAFLE, we are most excited about the possibility of applying the current workflow to samples in patients who are suffering from a disease. 

As mentioned, we first focused on the microbiomes sampled from people without overt disease, but now we would like to see what degree this economy of exchange is influencing disease risk and severity among the many diseases linked to altered microbial ecology.

Authorship: In addition to Nguyen, Mass General Brigham authors include Etienne Nzabarushimana. 

Paper cited: Hsu, T & Nzabarushimana, E (shared lead-authorship) et al. “Profiling lateral gene transfer events in the human microbiome using WAAFLE.” Nature Microbiology DOI: 10.1038/s41564-024-01881-w 

Funding: This work was supported by the National Institutes of Health (T32CA009001, U54DE023798, R24DK110499, and K23DK125838), the American Gastroenterological Association Research Foundation’s Research Scholars Award, the Crohn’s and Colitis Foundation Career Development Award, and the MGH/Chen Institute Transformative Scholars Award in Medicine. 

Disclosures: None declared.