Microbiome-Derived RNA Promotes Heritable Defense Against Intracellular Pathogens in Caenorhabditis elegans

Intestinal microbiota shape host immunity, but whether they can pre-activate defense against intracellular pathogens remains unclear. Here, we identify a natural microbiome member, Stenotrophomonas indicatrix JUb19, as the first example of a bacterium that partially induces the Intracellular Pathogen Response in Caenorhabditis elegans in the absence of infection. This response is coupled to broader metabolic remodeling, suggesting that combined immune and metabolic changes contribute to defense. We show that bacterial single-stranded RNA contributes to this effect, identifying a novel microbiome-derived signal that links microbial exposure to host defense. JUb19 exposure reduces susceptibility to both viral and microsporidian pathogens and confers inherited protection to unexposed progeny, but at a cost to parental fitness. These findings reveal a mechanism by which microbiome-derived RNA programs immunity against intracellular pathogens across generations.