The microbiota are vital for immune homeostasis and provide a competitive barrier to bacterial and fungal pathogens. Here, we investigated how gut commensals modulate systemic immunity and response to viral infection. Antibiotic suppression of the gut microbiota reduced systemic tonic type I interferon (IFN-I) and antiviral priming. The microbiota-driven tonic IFN-I-response was dependent on cGAS-STING but not on TLR signaling or direct host-bacteria interactions. Instead, membrane vesicles (MVs) from extracellular bacteria activated the cGAS-STING-IFN-I axis by delivering bacterial DNA into distal host cells. DNA-containing MVs from the gut microbiota were found in circulation and promoted the clearance of both DNA (herpes simplex virus type 1) and RNA (vesicular stomatitis virus) viruses in a cGAS-dependent manner. In summary, this study establishes an important role for the microbiota in peripheral cGAS-STING activation, which promotes host resistance to systemic viral infections. Moreover, it uncovers an underappreciated risk of antibiotic use during viral infections.

微生物群对于免疫稳态至关重要，并为细菌和真菌病原体提供竞争屏障。在这里，我们研究了肠道共生体如何调节全身免疫和对病毒感染的反应。肠道微生物群的抗生素抑制减少了全身性强直 I 型干扰素 (IFN-I) 和抗病毒启动。微生物群驱动的强直性 IFN-I 反应依赖于 cGAS-STING，但不依赖于 TLR 信号传导或直接的宿主-细菌相互作用。相反，来自细胞外细菌的膜囊泡 (MV) 通过将细菌 DNA 递送到远端宿主细胞中来激活 cGAS-STING-IFN-I 轴。在循环中发现了来自肠道微生物群的含有 DNA 的 MV，并以 cGAS 依赖的方式促进了 DNA（1 型单纯疱疹病毒）和 RNA（水疱性口炎病毒）病毒的清除。总之，该研究确定了微生物群在外周 cGAS-STING 激活中的重要作用，从而促进宿主对全身性病毒感染的抵抗力。此外，它揭示了在病毒感染期间使用抗生素的风险被低估了。