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Introduction:The intestinal microbiota helps to modulate host immune responses, with consequences for susceptibility to infectious disease and responses to vaccination. However, data on microbiome-immune interactions in healthy humans remains limited. Recently, mass vaccination campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) provided an unprecedented opportunity to study interactions between the healthy human microbiota and a defined, sterile and predictable immune response. Objectives: We aimed to understand (a) the influence of the microbiota on immune responsiveness to SARS-CoV-2 vaccination and (b) the impact of vaccine-induced immune activation on the microbiota. Patients & methods: The μHEAT (Microbial-Human Ecology And Temperature) study recruited 179 healthy adults 18-40 years old being vaccinated against SARS-CoV-2 between December 2021 and May 2022. Oral body temperature was measured by participants three times per day as a read-out of the innate immune response (fever). Serum antibodies were measured before and after vaccination as a reflection of the adaptive immune response. Six longitudinal fecal samples per person were subjected to shotgun metagenomic sequencing (N=1046) and a subset were further selected for metatranscriptomic sequencing (N=246) to profile microbiome composition and activity before and after the vaccine. Results: Fever responses to the vaccine were individualized and correlated with prior fever episodes, suggesting that certain people are more "fever-prone". Remarkably, the degree of fever was lower in participants who followed a plant-based diet. Furthermore, the baseline gut microbiome of individuals who experienced fever displayed a striking upregulation of flagellin gene expression, and an enrichment in flagellated Lachnospiraceae species. In contrast, anti-SARS-Cov2 antibody titres were not associated with diet or with flagellin expression, but correlated positively with abundance of the probiotic bacterium Streptococcus thermophilus. Conclusions: Expression of flagellin in the gut microbiota was strongly associated with fever responses to vaccination. Although causality remains to be established, we speculate that flagellin - a known ligand of innate immune receptors - may act as a natural adjuvant to stimulate fever. Together, these data improve our understanding of human immune- microbiome interactions, with implications for vaccine development.
