One of the most pressing problems in medicine today is the spread of antibiotic-resistant bacteria. Some scientists predict that we are entering a post-antibiotic world, one where virulent infections will be completely impervious to all the antibiotics we currently have available.
“Pathogens become multidrug resistant mainly by horizontal gene transfer, where they scoop up resistant genes from other organisms in their surroundings,” says Ilana L. Brito, Biomedical Engineering. “One way to tackle this problem is to stay a step ahead of the bacteria by understanding how they are picking up these genes.”
How Do Pathogens Become Antibiotic Resistant?
The human gastrointestinal system is thought to be a key site for the growth and spread of antibiotic resistance. Yet scientists know little about how that happens. One hypothesis is that pathogens pick up the resistant genes when they comingle in the gut with hundreds of thousands of other endemic organisms, some of which harbor antibiotic-resistant traits. “There are a number of ways pathogens can acquire these genes,” Brito explains. “They can swap them from another organism; the genes can be unattached and freely available in the environment, and the pathogen can import them directly; or sometimes there are viruses or plasmids that carry the genes from one host to another.”
Gene transfer happens all the time in the gut microbiome with different types of genes. In earlier work, for instance, Brito showed that some organisms in the human gut will acquire metabolic genes from their environment. Now in a series of projects, the Brito lab is investigating basic questions about the process of gene transfer: How often does it happen and under what conditions? Are there certain human behaviors, drugs we take, or conditions of the human body that facilitate transfer? Ultimately, Brito and her colleagues want to ascertain if there are ways to intervene in the transfer process and bring it to a halt.
Antibiotic Resistance in Global and Clinical Populations
In one project, the researchers are working with collaborators in India, Nepal, Guatemala, Mexico, and Brazil, aiming to understand the spread of antibiotic-resistant microbes in the microbiomes of different human populations around the world. “People in different countries have different organisms in their guts,” Brito says. “We are looking at variations in the mobile gene pools in these different environments to try to understand how antibiotic resistance gets spread around the world. We are asking, do the organisms all engage in gene transfer in the same way? And what repercussions do the spread of these antibiotic-resistant genes have on the different populations’ microbiome systems?”
“Many of these patients suffer from sepsis. We’re trying to understand which bacteria in their guts are carrying the resistance and how they interact with other bacteria and other pathogens that are also present in that environment.”
In a series of collaborations at Weill Cornell Medicine — one with Michael J. Satlin, Infectious Disease, and another with Carl V. Crawford, Gastroenterology — Brito pursues her gut microbiome studies with clinically important populations. With Satlin, she studies patients with leukemias, people who are at high risk for multidrug resistant infections. “Many of these patients suffer from sepsis,” she says. “We’re trying to understand which bacteria in their guts are carrying the resistance and how they interact with other bacteria and other pathogens that are also present in that environment.”
With Crawford, Brito looks at the triggers for horizontal gene transfer among patients with inflammatory bowel disease (IBD). “Long term, patients with IBD get more and more recalcitrant infections,” she says. “The infections can become more virulent, and virulence is something that is often acquired through this gene transfer process.”
Genome Sequencing Gut Bacteria
Given that human beings are colonized by an array of microorganisms — by some estimates as many as 100 trillion bacterial cells mostly in the gastrointestinal tract — it’s a tall order to study the interplay between them. “Right now most of this type of research is done with one or two organisms in a test tube,” Brito says. “With that method, researchers can test for the transfer of a single vector between two organisms and study the process, but my lab is trying to peer into the whole microbial system.”
To sequence the bacteria in a gut biome, the Brito lab depends on cutting edge technologies. Among the most common is shotgun genome sequencing. The DNA of an organism is broken up randomly into small fragments, then reassembled using computer programs that quickly sequence the genome. This is combined with transcriptomic techniques that look at the overall microbial community’s RNA transcripts, giving a snapshot in time of which cellular processes are active and which are dormant. “Almost all the approaches we take strive to use systems-level techniques like these that allow us to assay all the organisms at once or in a very high through-put manner,” Brito says.
Where Do the Bacteria in Our Bodies Come From?
Before she came to Cornell in 2016, Brito worked as a postdoctoral researcher with Eric Alm at the Massachusetts Institute of Technology. Together with Alm and an international cohort, she designed and carried out a large project in the Fiji Islands that sought to pinpoint how genes and organisms are spread between human microbiomes. As part of that project, she created a study, which is just wrapping up in 2018, to ascertain whether people share the microbes that live in their mouths and guts.
“When it comes to pathogens, we know a lot about how they are transmitted,” Brito says. “We know you can pick up pathogens through fecal-oral transmission and through sexual transmission. We know you can catch diseases through touching an open wound. We know some diseases are airborne. But we don’t really know where the bacteria in our bodies comes from. One hypothesis is that they are transferred when we kiss or hug someone, but some studies have shown that isn’t the case. Can they be transferred through the air? We don’t know. The source of our microbiome is an open book.”
Our Microbes and Global Health
Brito’s globally oriented work brings with it the challenge of connecting deeply with her international collaborators. To address that, she has created a week-long workshop and symposium, held on the Cornell campus in the summer of 2018. Called “Our Microbes, Our Global Health,” the program includes researchers from around the world, as well as Cornell faculty members. “My lab has a really big interest in understanding why microbiomes are so different in different parts of the world and the impact this has on people’s health,” Brito says. “We seek to broaden the scope of microbiome research, to be more inclusive, to really address some of the large global health problems that are likely impacted by microbiome compositions — things like susceptibility to infection, malnutrition, or obesity. With the help of our international collaborators who have local knowledge and expertise, we want to address these problems in the different locations where they exist and in the context of the microbiomes of the people who live there.”