Vaccines pack a punch: The shots save lives, but they can also often cause minor side effects such as muscle soreness, fatigue and fever. Researchers have long wondered why some people develop these reactions while others seem to skate by unaffected. The reason, it turns out, may have to do with the bacteria in our guts.
In a new study published in Science on Thursday, researchers collected stool samples from more than 170 people before and after a second or third dose of a COVID vaccine. They found that people who experienced fever after the shot tended to share similar microbiome traits.
Specifically, people with worse fever tended to have more of a protein called flagellin in their systems than those with little to no fever. Flagellin makes up the tail-like structures, or flagella, that bacteria use to move—suggesting that the fever-associated microbes had greater “motility,” or ability to move around, explains Ruth Ley, the study’s senior author and director of the department of microbiome science at the Max Planck Institute for Biology Tübingen in Germany. The participants with high-fever symptoms also tended to have greater gut inflammation than their peers.
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To investigate why, exactly, flagellin might influence fever, the researchers conducted a follow-up experiment in genetically engineered mice. They found that animals exposed to the fever-associated human bacteria showed a response equivalent to a fever in humans. This was particularly the case in those that could sense flagellin. Mice without flagellin receptors were less affected—indicating a direct link between flagellin and an immune system response.
On top of that, the levels of humans’ fever correlated with those of the equivalent reaction in mice, Ley says. “The worse the fever in the people, the more the temperature dropped in the mice,” she says. (Mice typically experience hypothermia as part of their immune response, which serves a similar function as a fever in humans.)
It’s still unclear why some people could have higher levels of flagellin in their guts than others. It may have something to do with diet: self-reported vegetarians tended to have lower flagellin levels, according to the study. But more research is needed to tease that out.
“It would make sense that, if you could tamp down the motility of the bacteria, we would predict that you wouldn’t react as strongly in terms of the fever,” Ley says. “But that’s all very much future research.”
Eventually, Ley hopes, the results could help fight this side effect of vaccines and, by extension, encourage higher vaccination rates.
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