Interactions between the microbiota and mammalian host are essential for defense against infection, but the microbial-derived cues that mediate this relationship remain unclear. Here, we find that intestinal epithelial cell (IEC)-associated commensal bacteria, segmented filamentous bacteria (SFB), promote early protection against the pathogen Citrobacter rodentium, independent of CD4⁺ T cells. SFB induced histone modifications in IECs at sites enriched for retinoic acid receptor motifs, suggesting that SFB may enhance defense through retinoic acid (RA). Consistent with this, inhibiting RA signaling suppressed SFB-induced protection. Intestinal RA levels were elevated in SFB mice, despite the inhibition of mammalian RA production, indicating that SFB directly modulate RA. Interestingly, RA was produced by intestinal bacteria, and the loss of bacterial-intrinsic aldehyde dehydrogenase activity decreased the RA levels and increased infection. These data reveal RA as an unexpected microbiota-derived metabolite that primes innate defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat infections.

微生物群与哺乳动物宿主之间的相互作用对于防御感染至关重要，但介导这种关系的微生物衍生线索仍不清楚。在这里，我们发现肠上皮细胞 (IEC) 相关的共生细菌、分段丝状细菌 (SFB) 促进了对病原体柠檬酸杆菌啮齿类动物的早期保护，与 CD4 ⁺无关T 细胞。SFB 在富含视黄酸受体基序的位点诱导 IEC 中的组蛋白修饰，表明 SFB 可通过视黄酸 (RA) 增强防御。与此一致，抑制 RA 信号抑制了 SFB 诱导的保护。尽管抑制了哺乳动物 RA 的产生，但 SFB 小鼠的肠道 RA 水平升高，表明 SFB 直接调节 RA。有趣的是，RA 是由肠道细菌产生的，细菌固有的醛脱氢酶活性的丧失会降低 RA 水平并增加感染。这些数据表明 RA 是一种意想不到的微生物群衍生代谢物，可启动先天防御，并表明使用益生菌和益生菌方法来提升 RA 可以预防或对抗感染。