STING N153S mouse stool microbiota Targeted loci environmental. STING N153S mouse stool microbiota

STING modulates immunity in response to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with STING gain-of-function mutations develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is characterized by inflammatory or fibrosing lung disease. We hypothesized that hyperresponsiveness of STING gain-of-function to bacterial CDNs might explain autoimmune lung disease in SAVI mice. Depletion of gut microbes with oral antibiotics (VNA; vancomycin, neomycin, ampicillin) nearly eliminates lung disease in SAVI mice and diminishes cytokine production, suggesting that gut microbes promote STING-associated autoimmunity. However, we also find that germ-free SAVI mice develop severe lung disease, and that transferring gut microbiota from antibiotics-treated mice to germ-free animals eliminates lung inflammation. Depletion of anaerobes by adding metronidazole eliminates the protective effect of the other antibiotics, and recolonization with the metronidazole-sensitive anaerobe Bacteroides thetaiotaomicron prevents disease, confirming a protective role of a metronidazole-sensitive microbe in a model of SAVI.