Gut Bacterial Flagellin Linked to Fever After mRNA COVID-19 Vaccination in Human Cohort, Mouse Models Implicate Diet

Why do some individuals develop a fever after vaccination while others experience no side effects? A new study published in Science identifies an unexpected contributor: a protein produced by specific gut bacteria.

Researchers from the Max Planck Institute for Biology Tübingen in Germany discovered that adults who experienced higher temperatures following mRNA COVID-19 vaccination harbored gut microbes that produced elevated levels of flagellin—the structural protein forming the whip-like flagella bacteria use for motility. The study monitored 171 healthy young adults, the majority of whom were receiving a third mRNA dose.

The finding provides a potential biological explanation for a common, typically transient side effect. The authors caution that the research does not demonstrate that dietary changes can prevent fever.

A Bacterial Protein That Primes Inflammation

Participants recorded their oral temperature three times daily for approximately two weeks surrounding vaccination, according to an earlier preprint. Researchers compared each individual’s readings against their own baseline temperature at the corresponding time of day.

Individuals with larger temperature increases exhibited more active flagellin genes in their gut microbiota prior to vaccination. A significant portion of this activity originated from the bacterial family Lachnospiraceae, as noted in a summary by News-Medical. These “high responders” also displayed elevated markers of low-grade inflammation in blood and stool samples at baseline.

Fever and flu-like symptoms are among the most frequent reactions to mRNA vaccines, yet their occurrence varies widely, and individuals who react strongly often do so consistently across doses. This reproducibility suggested an individual-specific factor, and the gut microbiome—which modulates systemic immune activity—was a logical candidate.

The immune system recognizes flagellin as a microbial signature, triggering inflammatory pathways. The researchers propose that sustained flagellin exposure from the gut maintains the immune system in a mildly primed state, causing a vaccine challenge to elicit a stronger febrile response in certain people.

Ruth Ley, Director of the Department of Microbiome Science at the institute, stated in a Max Planck Society release that “microbial flagellin is one contributor to this baseline immune state.”

Mouse Experiments and the Diet Question

To test causality, the team transplanted gut microbiota from study participants into germ-free mice. Mice receiving microbes from high responders developed larger temperature fluctuations and heightened inflammatory signaling after vaccination, an effect partially dependent on the animals’ ability to detect flagellin.

Diet emerged as a modulator in laboratory settings. Certain food additives increased flagellin production by gut bacteria in vitro, and a high-fat, Western-style diet exacerbated inflammatory vaccine reactions in mice. Co-author Benoît Chassaing of Inserm and Institut Pasteur remarked that the results suggest “components of an industrialized diet may promote the growth of flagellated gut bacteria.”

The researchers emphasized the limitations regarding human applicability. “While we could not show that diet determines vaccine responses in humans,” said lead author Kelsey Huus, who conducted the work at Max Planck, “the findings suggest diet is one factor that can shape an inflammatory microbiome.” She noted that human studies are required to determine whether dietary interventions can alter flagellin production and vaccine-associated fever.

In an accompanying Science Perspective, immunologist Bali Pulendran wrote that diet and microbial ecology are “not immutable,” raising the prospect that individuals might one day prepare for vaccination deliberately, as reported by News-Medical.

Fever and Antibody Responses

Flagellin levels, gut inflammation, and diet did not appear to influence antibody responses to the vaccines, the researchers reported. In other words, the gut factors associated with fever were not linked to diminished or enhanced antibody production.

This distinction is relevant because concern over side effects can discourage individuals from completing vaccination schedules. The work may eventually help clinicians explain why certain people consistently experience stronger reactions.

The evidence has clear constraints. The human findings are correlational, not causal, and dietary data were self-reported. Participants were healthy young adults, limiting generalizability to older populations, children, or those with chronic conditions. The food-additive findings derive solely from in vitro and mouse experiments, and the study focused on mRNA COVID-19 vaccines; it remains unknown whether the same pattern applies to influenza or other vaccines.

Practical Takeaways for Vaccine Season

For most people, side effects such as low-grade fever resolve within a few days and reflect the immune system responding to the vaccine. Rest, hydration, and over-the-counter antipyretics—if deemed appropriate by a clinician—are standard measures for managing discomfort.

Individuals should not alter their diet, take probiotics, or decline a recommended vaccine based on this study. No human trial has tested whether modifying gut bacteria prior to vaccination reduces side effects.

Medical attention should be sought for a high fever lasting more than a couple of days, difficulty breathing, swelling of the face or throat, chest pain, or a racing heartbeat after vaccination. While uncommon, these symptoms require prompt evaluation. Anyone with a history of strong reactions can discuss timing a shot before a day when rest is feasible with a clinician. MedicalDaily will report on human dietary studies when results become available.

Key Questions Answered

What did the Science study find?

Adults who developed higher temperatures after mRNA COVID-19 vaccines had gut bacteria that produced more flagellin, a protein capable of triggering inflammation.

What is flagellin?

Flagellin is the protein bacteria use to construct flagella, the tail-like structures enabling motility. The immune system recognizes it as a bacterial marker.

Does diet cause vaccine fever?

This was not demonstrated in humans. Food additives and a Western-style diet increased flagellin or inflammation in laboratory and mouse experiments, but human dietary trials have not been conducted.

Did gut bacteria affect vaccine protection?

The researchers found that flagellin, gut inflammation, and diet did not appear to affect antibody responses to the vaccines.

How many people were studied?

The study followed 171 healthy young adults, most receiving a third mRNA COVID-19 dose, supplemented by experiments in mice.

Should I take probiotics before a vaccine?

There is no evidence that probiotics or dietary changes reduce vaccine fever. Consult a clinician before making changes.

When is fever after a vaccine a concern?

Seek care for a high fever lasting more than a couple of days, trouble breathing, facial swelling, chest pain, or a racing heartbeat.

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