People differ markedly in their adverse responses to vaccination, but this variation is not well understood:
The gut microbiome has been implicated in adaptive immune responses to vaccination; we hypothesized that interactions between commensal gut microbes and the immune system may influence the risk of adverse inflammatory vaccine reactions.
The µHEAT (Microbial-Human Ecology and Temperature) Study longitudinally tracked 171 healthy young adults receiving severe acute respiratory syndrome coronavirus 2 mRNA vaccines. Thrice-daily oral temperature records were used to quantify fever, and fecal and serum samples were collected for microbiome and immune profiling. We found that fever had very little effect on the microbiome; by contrast, fever-positive participants displayed chronic low-grade intestinal inflammation and a microbiome characterized by high expression of bacterial flagellins, both pre- and postvaccination. Microbiomes from fever-positive participants induced heightened inflammatory responses in human colonic organoids and exacerbated acute vaccine responses when transplanted into gnotobiotic mice, and this was dependent on sensing of bacterial flagellin through host innate immune receptors. Moreover, microbial flagellin production was modifiable by diet: Dietary additives increased bacterial flagellin production in vitro, and a Western-style diet exacerbated vaccine reactions in mice. Consistent with this, fever was associated with dietary and metabolic markers in humans. Although interventional human studies are needed to establish causality, this suggests that diet modification could be a viable strategy to influence microbiome-dependent vaccine responses.