biostudies-literatureCampbell IWNIDDK NIH HHSNIAID NIH HHSHoward Hughes Medical Institute (HHMI)3069-3074https://www.ebi.ac.uk/biostudies/studies/S-EPMC12669028biostudies-literatureUnknown10(12)The natural context in which CRISPR-Cas systems are active in Enterobacteriaceae has remained enigmatic. Here we find that the Citrobacter rodentium type I-E CRISPR-Cas system is activated by the oxygen-responsive transcriptional regulator Fnr in the anoxic environment of the mouse intestine. Since Fnr-dependent regulation is predicted in ~41% of Enterobacteriaceae cas3 orthologues, we propose that anoxic regulation of CRISPR-Cas immunity is an adaptation that protects Enterobacteriaceae against threats from foreign DNA within the intestinal microbiome.Nature microbiologyAnoxia activates CRISPR-Cas immunity in the mouse intestine.PMC12669028R01 AI042347P30 DK034854Investigator programWaldor MKBasta DWZingl FGDoranga SSullivan EJCampbell IWfalseAnoxia activates CRISPR-Cas immunity in the mouse intestine.The natural context in which CRISPR-Cas systems are active in Enterobacteriaceae has remained enigmatic. Here we find that the Citrobacter rodentium type I-E CRISPR-Cas system is activated by the oxygen-responsive transcriptional regulator Fnr in the anoxic environment of the mouse intestine. Since Fnr-dependent regulation is predicted in ~41% of Enterobacteriaceae cas3 orthologues, we propose that anoxic regulation of CRISPR-Cas immunity is an adaptation that protects Enterobacteriaceae against threats from foreign DNA within the intestinal microbiome.2025-01-01T00:00:00Z2025 Dec2026-06-05T21:48:49.811Z2026-05-22T03:16:12.309ZS-EPMC126690284116265910.1038/s41564-025-02172-8