Gut Microbes Help Set Body’s Response To Vaccination

The human gut microbiome may help determine how strongly the immune system reacts to vaccination

To the Point

• The gut microbiome may shape vaccine responses: Differences in people’s gut microbes before vaccination are linked to how strongly they developed fever after vaccination.

• Microbial flagellin is a key contributor: Individuals with stronger fever responses produce more bacterial motility proteins, including flagellins, before vaccination. Transferring microbiomes from these individuals to mice drove stronger inflammatory responses to vaccination, partly through host sensing of flagellin.

• Diet may modify this microbiome-immune interaction: Diet could influence microbial flagellin production and mouse vaccine responses, although further studies are needed to establish whether changing diet can alter vaccine responses in humans.

• New insights into individual immune differences: The gut microbiome may help set an individual’s baseline immune tone, potentially influencing responses not only to vaccines but also to other immune challenges.

Vaccination is one of the most important tools for preventing infectious diseases and protecting public health. However, immune responses after vaccination vary dramatically from person to person: if you give many people the exact same vaccine, some will experience side effects such as fever and flu-like symptoms while others feel fine. The risk of side effects like fever can make people hesitant to be vaccinated, potentially reducing vaccination rates and increasing the risk of preventable illness and death. Fever reflects an inflammatory immune response; currently, however, it isn’t clear why only some people experience fever after vaccines.

Researchers at the Max Planck Institute for Biology Tübingen, Georgia State University, Institut Pasteur in Paris, the French National Institute for Health and Medical Research (Inserm), University of Manitoba, the University of California San Diego, and the Institute for Tropical Medicine at the University of Tübingen have now shown that one source of the variation in immune response may be the gut microbiome. The trillions of microorganisms inhabiting the human intestine differ between individuals and continually interact with the immune system. By interacting with our immune systems, these microorganisms help establish a person’s immune state even prior to vaccination.

To understand the role of the microbiome during vaccination, a team of researchers led by Ruth Ley in the Department of Microbiome Science at the Max Planck Institute for Biology Tübingen established the µHEAT (Microbial-Human Ecology and Temperature) study. With support from Meral Esen at the Institute of Tropical Medicine in Tübingen, the study recruited healthy young adults receiving a SARS-CoV-2 vaccine in 2021 and 2022. Participants provided fecal samples for microbiome profiling and blood samples for immune measurements, and regularly recorded their temperature in the week before and after vaccination.

“It was a challenging time to set up a new human study, with the pandemic ongoing,” says lead author Kelsey Huus, who led µHEAT for her postdoctoral work and is now Assistant Professor at the University of Ottawa in Canada. “We didn’t want to burden participants with too many measurements or visits, and it was a bit of a race against time to get the study organized before everyone was already vaccinated. But it was absolutely worth it, because the project yielded some very exciting results.”

A microbial signature before vaccination

As expected, participants differed markedly in their temperature responses, and some developed a substantial fever. Interestingly, several factors distinguished these higher fever responders even before their vaccination. Most notably, the microbiomes of participants who subsequently developed stronger fever responses showed increased activity of bacterial motility genes, particularly genes used to make the whip-like flagella for bacterial swimming.

Bacterial flagella-the structures that allow many bacteria to swim-are made of small proteins called flagellins. Because flagellins are also produced by pathogenic bacteria such as Salmonella, the human immune system recognizes them as potentially dangerous signals, and responds with inflammation.

Importantly, these microbiome differences were already present before vaccination. Participants with stronger fever responses also showed evidence of a more inflammatory baseline state, including differences in inflammatory markers in blood and fecal samples. Together, the observations suggested that microbial flagellin production might contribute to an individual’s pre-existing immune tone and thereby influence the response to vaccination.

Testing whether the microbiome can drive the response

The researchers performed a classic microbiome experiment to test if the microbiome affects the immune response: they transferred fecal microbiomes from study participants into mice that lacked their own intestinal microbes. These mice were then vaccinated, to determine whether the microbiome alone could cause differences in vaccine responses.

Indeed, mice that received microbiomes from study participants that experienced strong fever responders developed worse inflammation after their vaccine, compared to mice receiving microbiomes from those with milder responses. Moreover, the effect was partly dependent on the animals’ ability to sense microbial flagellin, providing evidence that flagellin contributes to the inflammatory vaccine response.

Together, the experimental findings suggest that the gut microbiome can help set the inflammatory state of the host before vaccination, with microbial flagellins contributing to the strength of the inflammatory vaccine response.

Could diet modify this immune tone?

The researchers also investigated why some microbiomes produced more flagellin in the first place, focusing on diet as one potential factor. Study participants eating plant-based diets tended to have weaker fever responses after vaccination. The researchers therefore tested whether dietary factors could influence microbial flagellin production. “We could see that certain food additives increased flagellin production by gut microbes in vitro,” Benoit Chassaing, Inserm Research Director at Institut Pasteur explains. “Interestingly, these findings show that components of an industrialized diet may promote the growth of flagellated gut bacteria and increase overall flagellin production.”

Hirohito Abo, a co-author from Georgia State University in Atlanta, underscores the broader implications of diet in the immune response to vaccination: “We found that a high-fat Western-style diet enhanced inflammatory vaccine responses in mice.”

“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” summarizes Kelsey Huus. “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.”

The microbiome helps set immune tone

“Vaccination provides a controlled way to understand why people can respond so differently to the same immune challenge,” says Ruth Ley, Director of the Department of Microbiome Science. “Our findings show that microbial flagellin is one contributor to this baseline immune state, providing a potential link between differences in the gut microbiome and differences in immune responses.”

In the future, interventions that target the microbiome could be tested to try and reduce strong fever responses after vaccination, which could help to address concerns that contribute to vaccine hesitancy. Moreover, the µHEAT study suggests that the microbiome may help set an individual’s immune tone, with implications for how people respond to a range of immune challenges beyond vaccination.

“Ultimately, this work adds to growing evidence that the gut microbiome plays a central role in human immune health,” Kelsey Huus adds. “Understanding these interactions could now open new opportunities to improve how we predict, prevent and manage individual differences in immune responses.”