Intermicrobial Antagonism Controls Essential Bacteria Populations in Human Guts

Mougous, John F. Enders Professor of Microbial Pathogenesis at Yale School of Medicine (YSM), studies bacterial warfare, or how different microbes defend their ecological niches against other species. This is an ancient form of conflict, honed over bacteria's billions of years of evolution. But compared to how microbes interact with human cells and systems, how they interact with other bacteria has been little studied.

Intermicrobial antagonism means everything when it comes to which bacteria live where. These microbe-microbe interactions affect which species colonize our guts, whether or not we can fight off pathogenic bacteria, and which bacteria might infect an open wound. They also have major implications for agriculture, including animal husbandry and the health of plant crops.

Some of these interactions could be exploited to create new laboratory tools-the gene-editing breakthrough CRISPR came from a natural bacterial system evolved to fight off viruses. Many clinically used antibiotics come from these natural attack and defense systems, but we haven't mined anywhere near the full arsenal bacteria have evolved. Better understanding microbial warfare could lead to new, better antibiotics.

It's an arms race that's been going on for billions of years, and so there are many molecular innovations that have come out of that. This is a really fundamental facet of bacterial life, but for a long time the ubiquity of this type of interaction wasn't fully understood."

Joseph Mougous, Professor of Microbial Pathogenesis, Yale School of Medicine

In chasing down the minutiae of bacterial antagonism, Mougous and his laboratory team have followed a number of different, circuitous pathways. Their work ranges from detailed three-dimensional structures of individual molecules to studies of entire communities of different bacterial species. Along the way, Mougous has led discoveries about an entirely new class of bacterial toxins called umbrella toxins, showed that a bacterial attack system thought to be aimed at human cells is actually aimed at other microbes, helped develop a new gene-editing technique, and figured out a method to study a mysterious class of extra-small bacteria.

In the summer of 2025, Mougous moved his laboratory team from the University of Washington in Seattle, where he'd been on the faculty of the Department of Microbiology for 17 years, to join YSM as a member of the Department of Microbial Pathogenesis and the Microbial Sciences Institute at Yale's West Campus.

"What is really striking about the Mougous Lab's work is the range of approaches they take," says Andrew Goodman, PhD, director of Yale's Microbial Sciences Institute and chair of the Department of Microbial Pathogenesis. "Joseph is trained in structural biology and biochemistry, but he also thinks about questions in microbial ecology and population dynamics. He's really fearless when it comes to thinking along that entire spectrum. His work has not only changed how we think about microbial interactions from the ecology perspective, but also identified completely unexpected biochemistry."

The Deceptive Simplicity of Bacteria

Mougous grew up in Grays Harbor, a quiet logging community on the coast of Washington state most famous as the birthplace of Kurt Cobain. Mougous had an innate love of nature throughout his childhood-his favorite TV shows were David Attenborough's nature documentaries-but didn't develop a direct interest in science until college at Western Washington University, where he studied biochemistry.

He stumbled into microbiology through his PhD studies in the laboratory of Nobel Laureate and chemist Carolyn Bertozzi, PhD, who was then at the University of California, Berkeley. At that time, Bertozzi was studying enzymes that modify human cell surface carbohydrates, and Mougous found some of these same enzymes in Mycobacterium tuberculosis, the bacteria that causes tuberculosis infections. That work sparked an interest in bacteria, which Mougous says he was drawn to by their supposed simplicity-one that has turned out to hide worlds of complexity.

"Early on, the simplicity of single-celled organisms seemed like something I could wrap my head around, but the more I've gotten into microbiology, the more I realize that bacteria are not as simple as I initially thought," he says. "I think if I had been smacked then with what I know now, I might have backed out of microbiology altogether!"

During his postdoctoral fellowship at Harvard University in the laboratory of microbiologist John Mekalanos, PhD, Mougous made key insights into a toxin secretion system in the infectious bacteria Pseudomonas aeruginosa, which can cause serious illness in people with compromised immune systems. Scientists initially thought that the bacteria used that system, called the type VI secretion system, to infect its human host cells. But the data didn't quite add up, Mougous says.

In 2007, he joined the faculty at the University of Washington and launched his independent lab focused on the study of bacterial warfare. Soon after, Mougous discovered that the type VI system is actually used to attack other bacteria. That discovery opened up a new professional world for Mougous. His research team realized that this potent secretion system is present in many other bacterial species as well.

"We were just at the tip of the iceberg. I thought it was a rich area of investigation and I was excited to be at the forefront of that," Mougous says.

Following his discovery about the type VI secretion system, the field of interbacterial conflict exploded. But Mougous has continually found new projects and research directions at the leading edge of the field.

"Bacterial conflict is like a playground for someone interested in finding new molecular mechanisms," he says.

For much of his career leading a research laboratory, Mougous has worked alongside S. Brook Peterson, PhD, a senior scientist who joined his lab team in 2013. Peterson acts as co-lead of his lab in many ways, Mougous says, helping him brainstorm research ideas, mentor trainees, and draft scientific papers and funding applications.

"We've worked on a very wide range of topics together over the years," Peterson says. "We're always looking for the next interesting question. A lot of scientists pick one system and that's what they stick to, but what sets Joseph apart is his willingness to tackle big questions and always reinvent himself."

From Parasitic Bacteria to Mitochondrial Genes

Mougous' ability to pivot to new research projects and his willingness to tackle new methods and areas of microbiology have paid off: He's led the publication of several scientific papers in high profile journals, including Nature, Science, and Cell. He was appointed as an investigator in the Howard Hughes Medical Institute in 2015, and in 2022 as a member of the National Academy of Sciences, which had also given him their prestigious award in molecular biology the previous year.

In recent years, Mougous and his laboratory team have made innovative findings in many areas of bacterial warfare. They discovered a new class of bacterial toxins, which they dubbed umbrella toxins because they have a central post and five radiating spikes from the top of that post, like the frame of an umbrella. In a subsequent study, published earlier this year, the scientists showed that the umbrella particles give bacteria an incredible arsenal of different, highly specific toxins to deploy all at once against a wide variety of enemy microbes.

In another project, Mougous is exploring a common but highly mysterious form of extra-small bacteria known as Patescibacteria, symbiotic bacteria that leech off larger bacteria. Sometimes called nanobacteria, these microbes make up around 15% of all bacterial species but are rarely studied due to the difficulty of culturing them in the lab.

Mougous and his team figured out a way to genetically manipulate a novel species of Patescibacteria that lives in the human mouth, Southlakia epibionticum. That new method allowed them to uncover the genetic basis for the Patescibacteria's growth on its host species. The Mougous Lab is now using their new system to answer questions about how Southlakia steals nutrients and other molecules from its host.

In a finding with implications for molecular biology and gene therapy, Mougous co-led a team that developed a novel tool to edit genes inside mitochondria, the organelles that provide all our cells' energy. Although most of our genes are housed in our nuclear genome, mitochondria have their own tiny genomes, and previous gene-editing techniques didn't work on mitochondrial DNA. CRISPR needs to be paired with a second molecule called a guide RNA to target the editor to the right DNA sequence, but guide RNAs can't get inside mitochondria.

The Mougous Lab discovered a novel DNA-targeting bacterial toxin that acts on double-stranded DNA and thus doesn't require CRISPR to work. Through collaborations with gene editing specialists at the Broad Institute of MIT and Harvard, they developed that bacterial toxin into a non-toxic molecular tool that successfully edited mitochondrial genes in human cells in the lab. This method is now being used for scientific studies of genes that had previously been out of reach with traditional gene editing and could one day lead to gene therapies for human mitochondrial diseases.

A New Start

Mougous was drawn to Yale, and the Microbial Sciences Institute in particular, by the collaborative, interdisciplinary nature of scientific research on the campus. The institute's mixture of structural biology, chemistry, computational modeling, genetics, and evolutionary biology fits well with his own broad research interests, Mougous says. He's already spurred by his new scientific surroundings.

"I've always felt like a change of scientific environment can inspire-new ideas, new colleagues with new input, new collaborative opportunities," he says.

Goodman and his colleagues were delighted to welcome not only Mougous, but his entire laboratory team; many of his lab members, including Peterson, moved from Seattle to New Haven along with him.

"There are so many links between Yale's strength in structural biology, microbial cell biology, and microbial pathogenesis. All of these establish a really excellent environment for the next phase of his lab," Goodman says. "It's been fantastic to have the whole group here."