Scientists have uncovered a shared target used by multiple diarrhea-causing bacteria to invade the gut.
Despite decades of research, scientists still do not have vaccines against two of the world’s most common causes of severe bacterial diarrhea: enterotoxigenic E. coli (ETEC) and Shigella. Together, these pathogens infect hundreds of millions of people each year and are responsible for substantial childhood illness and death, particularly in low-resource regions.
One reason vaccine development has proven so difficult is that the bacteria constantly vary the surface molecules that vaccines typically target. But researchers at Washington University School of Medicine in St. Louis have now uncovered a shared vulnerability hidden beneath those differences, raising the possibility of a single vaccine that could protect against both pathogens.
Scientists from WashU Medicine, the University of Missouri, and the International Centre for Diarrhoeal Disease Research in Bangladesh discovered that enterotoxigenic E. coli (ETEC), Shigella, and several other diarrhea-causing bacteria depend on three closely related enzymes to break through the protective mucus lining of the intestines. By analyzing samples from infected patients and volunteers exposed to the bacteria, the team found that antibodies directed at a common region shared by these enzymes could neutralize all three and prevent the bacteria from crossing the mucus barrier.
The findings, published in PNAS, suggest that a single vaccine could potentially provide protection against multiple major causes of severe diarrhea.
“For something so common and so deadly to young children, it’s striking that we still don’t have a vaccine for either of these pathogens,” said James M. Fleckenstein, MD, a professor of medicine in the Division of Infectious Diseases at WashU Medicine and co-senior author of the study. “What’s exciting here is that we’ve found a kind of Achilles’ heel or weak point they share that we might be able to target to protect against both.”
How the Bacteria Break Through the Gut’s Defenses
To trigger disease, intestinal pathogens must first get through the thick mucus layer that coats the gut. This protective barrier helps keep both harmful microbes and the body’s beneficial bacteria away from intestinal tissue. According to Fleckenstein, blocking pathogens at this stage could prevent infection without disrupting healthy microorganisms.
ETEC, which causes gastrointestinal illness unlike the many harmless strains of E. coli, and Shigella use closely related enzymes to break down a key protein in intestinal mucus. Once that barrier is compromised, the bacteria can release toxins that lead to diarrhea.
Fleckenstein’s laboratory previously identified one of these enzymes, called EatA, in disease-causing E. coli. The new study shows that two related enzymes, SepA and Pic, produced by Shigella and other diarrhea-causing bacteria, serve the same purpose by helping bacteria penetrate the mucus layer.
Antibodies Reveal a Common Weak Point
Working with coauthor Ali Ellebedy, PhD, the Leo Loeb Professor in the WashU Medicine Department of Pathology & Immunology, the researchers isolated antibodies from Bangladeshi patients naturally infected with ETEC as well as volunteers who participated in controlled infection studies.
The team found that antibodies capable of blocking EatA also neutralized SepA and Pic. Antibodies are proteins produced by the immune system that recognize specific targets and help eliminate them.
Researchers at the University of Missouri, including first author David P. Buckley, PhD, a postdoctoral research associate, then used cryo-electron microscopy, a technique that rapidly freezes molecules to capture highly detailed images, to determine where the most effective antibodies attached to the enzymes.
They identified a shared region present in all three enzymes. This common structure explains how a single antibody can disable the mucus-degrading tools used by several pathogens. It also provides vaccine developers with a specific target that could stimulate the immune system to produce protective antibodies before exposure to infection.
“This study establishes EatA as a viable vaccine candidate capable of providing protection across multiple pathogens,” said Zachary Berndsen, PhD, an assistant professor of biochemistry at the University of Missouri and co-senior author of the study. “By identifying the key regions of EatA that are targeted by neutralizing antibodies capable of inhibiting its enzymatic function, we’ve established a foundation for rational vaccine design — a major advance toward development of effective therapeutics that have the potential to save many lives.”
Toward a Broader Vaccine Strategy
The research builds on earlier studies involving children in Dhaka, Bangladesh. Those studies found that children who naturally developed antibodies against EatA were less likely to become ill, while children without those antibodies faced a higher risk of infection.
The need for effective vaccines extends well beyond developing countries. ETEC has been linked to major foodborne outbreaks in the United States. Because clinical laboratories often struggle to distinguish it from harmless E. coli strains, many infections may go undetected. Fleckenstein also noted that treating these infections with antibiotics contributes to the growing problem of antibiotic resistance.
Researchers are now working to advance the discovery toward vaccine development.
“These bacteria have evolved right alongside us, and they’ve gotten very good at breaching our defenses,” Fleckenstein said. “If we can block that first step, we have a chance to stop these infections before they ever take hold.”
Reference: “Human enterotoxigenic Escherichia coli (ETEC) infections elicit antibodies that broadly neutralize mucinases of pathogenic Escherichia coli and Shigella” by David P. Buckley, Marjahan Akhtar, Mahima Thapa, Aaron Schmitz, Jackson Turner, Tim J. Vickers, Nazia Khatoon, M. Hasanul Kaisar, Jonathan A. Coggin, Debayan Ganguli, Alaullah Sheikh, Renee M. Laird, Frédéric Poly, Chad K. Porter, Fernando Ruiz-Perez, Mark J. Miller, Fahima Chowdhury, Tafiqur R. Bhuiyan, Firdausi Qadri, Sergio Trillo-Muyo, Brendan Dolan, Sjoerd van der Post, Ali Ellebedy, Zachary T. Berndsen and James M. Fleckenstein, 15 June 2026, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2614012123
This work is supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), grant numbers R01 AI089894 and R01 AI126887, and by the Department of Veterans Affairs, grant number 5I01BX001469-05. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Department of Veterans Affairs.
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