AimsThis study aims to explore how feuD mutation triggered the increase in nisin immunity of Lactococcus lactis L58, which was proven to be a feuD::Em-Mu mutant of Lc.lactis N8. Methods and ResultsThe significant difference genes of Lc.lactis L58 and Lc.lactis N8 were compared at transcription and protein levels. Analysis revealed that the feuD mutation induced decrease in histidine-containing phosphocarrier protein PtsH (HPr) and increase in thioredoxin reductase TrxB (TR). Determination of iron concentration and cytoplasmic membrane potential (MP) showed the iron concentration decreased around 10% and the MP decreased approx. 14% in Lc.lactis L58. ConclusionsThe increase in nisin immunity was dominated by TR up-expression by two main mechanisms in Lc.lactis L58. First, the TR-TRX (thioredoxin reductase) system changed the composition of cytoplasmic membrane by regulating the lipid metabolism to enhance the cells' resistance to nisin. Second, iron starvation stress induced decrease in MP; hence, the binding affinity of nisin to lipid II of Lc.lactis L58 decreased, which, in turn, increased the nisin immunity. Significance and Impact of the StudyThe knowledge on regulation mechanism of nisin immunity was enriched, and the theoretical basis for improving nisin production in engineering strain could be provided.