"Vaccination provides a controlled way to understand why people can respond so differently to the same immune challenge," said Ley, who directs the Department of Microbiome Science. "Our findings show that microbial flagellin is one contributor to this baseline immune state."

Could the microbiome actually cause the difference?

To test causality, the team transplanted fecal microbiomes from participants into mice raised without their own gut bacteria, then vaccinated the animals. Mice that received microbiomes from high-fever donors developed more inflammation after vaccination than those receiving microbiomes from low-fever donors. Blocking the animals' ability to sense flagellin partly erased that effect, supporting the idea that the protein — not just the broader microbiome — drives part of the response.

Does diet play a role?

The researchers also asked why some microbiomes produce more flagellin in the first place. Participants who ate plant-based diets tended to have milder fevers. In culture dishes, certain food additives increased flagellin production by gut microbes.

"We could see that certain food additives increased flagellin production by gut microbes in vitro," said Benoit Chassaing, an Inserm research director at Institut Pasteur. "These findings show that components of an industrialized diet may promote the growth of flagellated gut bacteria and increase overall flagellin production."

In mouse experiments, a high-fat Western-style diet amplified inflammatory vaccine responses. "We found that a high-fat Western-style diet enhanced inflammatory vaccine responses in mice," said co-author Hirohito Abo of Georgia State University in Atlanta.

The authors caution that the human dietary data are observational. "While we could not show that diet determines vaccine responses in humans, our study findings suggest that diet is one factor capable of modifying a pro-inflammatory microbiome," Huus said. "Interventional studies in people will be needed to determine whether dietary changes can alter microbial flagellin production in humans and, in turn, vaccine responses like fever."

What's next?

Future work should test whether reshaping the microbiome — through diet, probiotics, or other interventions — can blunt the fevers and side effects that discourage vaccination, the researchers said. "Ultimately, this work adds to growing evidence that the gut microbiome plays a central role in human immune health," Huus added. "Understanding these interactions could now open new opportunities to improve how we predict, prevent and manage individual differences in immune responses."

The study was a collaboration among the Max Planck Institute for Biology Tübingen, Georgia State University, Institut Pasteur, Inserm, the University of Manitoba, the University of California San Diego, and the Institute for Tropical Medicine at the University of Tübingen.