Gut microbes may help shape how strongly the body responds to vaccination. Flagellins produced by motile gut bacteria can promote inflammation and contribute to differences in fever responses after vaccination.
Graphic Credit: © MPI f. Biology Tübingen / 99Designs
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Scientific Frontline: Extended "At a Glance" Summary: Gut Microbiome and Vaccine Response
The Core Concept: The human gut microbiome helps determine the baseline inflammatory state of an individual's immune system, which subsequently influences the severity of their reaction to vaccinations.
Key Distinction/Mechanism: While vaccines elicit an immune defense, the presence of bacterial flagellins—motility proteins produced by motile gut microbes—acts as a pre-existing danger signal that predisposes the host to a stronger inflammatory response, such as a fever.
Origin/History: This immunological link was demonstrated during the µHEAT (Microbial-Human Ecology and Temperature) study, which profiled the microbiomes and immune responses of young adults receiving SARS-CoV-2 vaccines in 2021 and 2022.
Major Frameworks/Components:
- Microbial flagellins: Small proteins making up the whip-like flagella used for bacterial swimming, which the human immune system recognizes as a threat similar to pathogenic Salmonella.
- Baseline immune tone: The pre-established inflammatory state of the host prior to receiving a vaccine.
- Dietary modulation: The capacity for dietary factors, such as high-fat or industrialized diets, to increase the growth of flagellated bacteria, compared to plant-based diets that correlate with milder fever responses.
- Microbiome transfer: Experimental models showing that germ-free mice adopt the specific inflammatory vaccine response profile of their human microbiome donors.
Branch of Science: Immunobiology, Medicine, and Microbiology.
Future Application: Developing targeted dietary or microbiome interventions to minimize vaccine side effects, thereby reducing vaccine hesitancy and predicting individual responses to various immune challenges.
Why It Matters: Understanding how gut bacteria govern baseline immunity provides a crucial pathway to improving vaccine comfort, personalizing preventive medicine, and protecting public health.
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 many people receive 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 is not 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 system, 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 they 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 an assistant professor at the University of Ottawa in Canada. “We did not 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 preexisting 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 whether 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 who experienced strong fever responses 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 coauthor 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 proinflammatory 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 to 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.”
Published in journal: Science
Title: The human gut microbiome primes fever after vaccination
Authors: Kelsey E. Huus, Μheat Study Group, Hirohito Abo, Yi Han Tan, Ezgi Atay, Héloïse Rytter, Ronald Keller, Silke Dauser, Dai Long Vu, Meghan B. Azad, Rob Knight, Alfred Ke, Larisa Lotoski, Marc-André Langlois, Rong Liu, Alexander V. Tyakht, Nicholas Youngblut, Sang-Moo Kang, Julie Parsonnet, Lisa Maier, Benoit Chassaing, Peter G. Kremsner, Andrew T. Gewirtz, Meral Esen, and Ruth E. Ley
Source/Credit: Max-Planck-Gesellschaft
Edited by: Scientific Frontline
Reference Number: imgy100826_01