Gut microbes may help explain fever after vaccination

Clinical takeaway: When counseling patients concerned about vaccine reactions, explain that gut microbes may influence whether they develop fever after vaccination, without necessarily affecting the antibody boost. The findings suggest a potential path toward reducing side effects through dietary or microbiome interventions.

Fever and flu-like symptoms after vaccination can discourage patients from returning for future doses. A study in Science suggests that gut microbes may help explain why some people consistently experience stronger reactions.

Researchers followed 171 healthy adults aged 18–40 receiving mRNA COVID-19 vaccines, mostly third doses. Participants recorded oral temperatures three times daily and provided stool and blood samples.

Larger temperature rises were associated with persistent, low-grade intestinal inflammation and greater production of flagellin, a protein that forms the structures bacteria use to move. Flagellin can activate inflammatory immune pathways, potentially priming the body for a stronger reaction to vaccination.

Experiments supported this mechanism: bacterial products from participants with larger temperature rises triggered stronger inflammatory responses in human intestinal cell models. Transferring their gut microbes into mice also intensified inflammatory vaccine reactions.

“Together, our results establish the possibility of microbiome-targeted interventions to attenuate vaccine-induced adverse events,” the study authors wrote.

Diet emerged as a possible influence. The 46 participants reporting vegetarian or vegan diets had smaller temperature rises than other participants. Dietary additives increased bacterial flagellin production in laboratory experiments, and a Western-style diet worsened vaccine reactions in mice. However, the study did not test whether changing people’s diets before vaccination reduced symptoms.

The microbiome features associated with stronger reactions were not consistently linked to stronger antibody responses. The relative antibody increase after vaccination was also similar between participants with larger and smaller temperature rises, suggesting that inflammation and antibody boosting may be partly separable.

Human intervention trials are needed to determine whether dietary or microbiome changes can safely improve vaccine tolerability while preserving protective immunity.

“Diet, microbial ecology, and the metabolic state are not immutable, and people might one day prepare for vaccination as deliberately as the vaccine itself is formulated,” wrote Bali Pulendran of Stanford University School of Medicine in an accompanying perspective article.

Source: Huus KE, et al. (2026 Oct 8) Science. The human gut microbiome primes fever after vaccination