Abstract

The de‐repression of transposable elements (TEs) in mammalian genomes is thought to contribute to genome instability, inflammation, and ageing, yet is viewed as a cell‐autonomous event. In contrast to mammalian cells, prokaryotes constantly exchange genetic material through TEs, crossing both cell and species barriers, contributing to rapid microbial evolution and diversity in complex communities such as the mammalian gut. Here, it is proposed that TEs released from prokaryotes in the microbiome or from pathogenic infections regularly cross the kingdom barrier to the somatic cells of their eukaryotic hosts. It is proposed this horizontal transfer of TEs from microbe to host is a stochastic, ongoing catalyst of genome destabilization, resulting in structural and epigenetic variations, and activation of well‐evolved host defense mechanisms contributing to inflammation, senescence, and biological ageing. It is proposed that innate immunity pathways defend against the horizontal acquisition of microbial TEs, and that activation of this pathway during horizontal transposon transfer promotes chronic inflammation during ageing. Finally, it is suggested that horizontal acquisition of prokaryotic TEs into mammalian genomes has been masked and subsequently under‐reported due to flaws in current sequencing pipelines, and new strategies to uncover these events are proposed.