Enhanced Oral Vaccination with Competitive Gut Bacteria

Scientists are combining vaccines with harmless gut bacteria to fight infections more effectively—offering a potential breakthrough in the battle against antibiotic resistance.

The gut microbiome is a complex environment. While beneficial bacteria help us digest food, the intestine can also harbor harmful microbes that cause illness. Some of these pathogens can remain dormant for long periods before turning dangerous—particularly if the immune system is compromised, the intestinal lining is damaged, or bacteria enter the bloodstream through injuries. This can lead to serious conditions like blood poisoning or organ inflammation.

Vaccines that protect the intestines from harmful bacteria—especially antibiotic-resistant strains—have long been a research goal. But designing them is difficult: the gut’s immune system functions differently from the rest of the body, and much about it remains poorly understood.

A Powerful Combination

Emma Slack, a professor at the Sir William Dunn School of Pathology at the University of Oxford and ETH Zurich, is tackling this challenge. Alongside a global team of researchers, including Médéric Diard from the University of Basel’s Biozentrum, she’s developed a promising new approach: oral vaccines combined with benign bacteria that outcompete harmful microbes.

In a study published in Science, the researchers demonstrated in mice that this dual approach could both prevent colonization by salmonella and eliminate established E. coli infections—results that neither vaccination nor competitive bacteria could achieve alone.

The key lies in introducing rival bacterial strains that are adapted to live in the same gut environment as the pathogens. To compete effectively, these strains must consume the same nutrients, thrive in the same regions of the intestine, and tolerate similar levels of acidity and oxygen.

The team achieved this by selecting or engineering bacterial strains that closely mimic the behavior of the target pathogens. In some cases, genetic engineering was used to develop an effective salmonella competitor. In others, a carefully selected blend of three naturally occurring E. coli strains proved just as effective—without any genetic modification.

“Although we can decimate pathogenic bacteria with a vaccine, we need harmless microorganisms to fill the resulting niche in the intestinal ecosystem to achieve long-term success,” said Slack.
“It’s like gardening—if you pull weeds but don’t plant anything in their place, the weeds just grow back.”

Beyond the Lab

Previous research has shown that some people naturally carry gut bacteria that suppress dangerous strains. In such individuals, vaccines against intestinal pathogens tend to work better. By including competitor strains in the vaccine, the new method could help people without this natural advantage achieve similar protection.

One of the most promising aspects of this approach is that it works without antibiotics—and is effective even against antibiotic-resistant bacteria, which are a growing public health threat.

This strategy could be especially useful in high-risk medical scenarios, such as organ transplants, where patients take immunosuppressive drugs that make them vulnerable to infections. It could also help reduce the need for prophylactic antibiotics before surgery or travel to regions where the immune system may be unprepared for unfamiliar bacterial strains.

“In general, the more successful we are in decimating harmful and antibiotic-resistant strains in the population, the better it is for the health of everyone,” Slack said.

Eventually, this approach could take the form of a simple capsule containing both the vaccine and the protective bacteria. But before that happens, more research is needed—especially to adapt the method for clinically relevant microbes and human subjects.

In the current study, the team used model pathogens to demonstrate proof of concept. The next step will be translating these results to the real-world bacteria that cause human disease.