Transferrable protection by gut microbes against STING-associated lung disease

• Published in: Cell reports (Cambridge) 2021-05, Vol.35 (6), p.109113-109113, Article 109113
• Main Authors: Platt, Derek J., Lawrence, Dylan, Rodgers, Rachel, Schriefer, Lawrence, Qian, Wei, Miner, Cathrine A., Menos, Amber M., Kennedy, Elizabeth A., Peterson, Stefan T., Stinson, W. Alexander, Baldridge, Megan T., Miner, Jonathan J.
• Format: Article
• Language: English
• Subjects: Animals; autoimmunity; Bacteroides; cGAMP; cGAS; Gastrointestinal Microbiome - physiology; Humans; lung disease; Lung Diseases - physiopathology; Mice; microbiome; microbiota; Mutation; SAVI; Signal Transduction; STING
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109113

STING modulates immunity by responding 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 gain-of-function STING to bacterial CDNs might explain autoinflammatory lung disease in SAVI mice. We report that depletion of gut microbes with oral antibiotics (vancomycin, neomycin, and ampicillin [VNA]) nearly eliminates lung disease in SAVI mice, implying that gut microbes might promote STING-associated autoinflammation. However, we show that germ-free SAVI mice still develop severe autoinflammatory disease and that transferring gut microbiota from antibiotics-treated mice to germ-free animals eliminates lung inflammation. Depletion of anaerobes with metronidazole abolishes the protective effect of the VNA antibiotics cocktail, 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. [Display omitted] •Oral antibiotics prevent lung disease in STING gain-of-function (SAVI) mice•Germ-free conditions do not protect against autoinflammatory disease•Transfer of Bacteroidales-rich microbiota to germ-free SAVI mice confers protection Platt et al. report that oral antibiotics but not germ-free conditions prevent autoinflammatory lung disease in a mouse model of STING-associated vasculopathy with onset in infancy (SAVI). Recolonization of SAVI mice with either Bacteroidales-enriched stool or Bacteroides thetaiotaomicron is protective in this model of STING-associated autoinflammatory lung disease.