Entry 25
Probiotic science page
Produces nisin and serves as a genetic chassis for therapeutic protein delivery, with food preservation and vaccine applications.
Overview
Lactococcus lactis subsp. lactis IL-1403 and subsp. cremoris MG1363 are the two most thoroughly studied prototype strains of the genus Lactococcus. They serve as the primary model organisms for lactic acid bacteria genetics, physiology, and metabolic engineering [1,3]. Both strains have complete genome sequences. Bolotin et al. (2001) sequenced IL1403 (2.365 Mb) as the first lactic acid bacterium genome [1]. Wegmann et al. (2007) sequenced MG1363 (2.53 Mb) [2]. Certain L. lactis subsp. lactis strains produce nisin. These include the closely related NCDO 712 derivative IL1403 lineage. Nisin is a Class I bacteriocin widely used as a food preservative (E234) [6]. L. lactis is also a key platform for delivering recombinant proteins. These include therapeutic cytokines such as IL-10 [4,5].
Mechanism
L. lactis ferments hexose sugars and produces only lactic acid from sugar. It converts pyruvate to L-lactate through lactate dehydrogenase. Control of glycolytic flux is distributed across multiple enzymes. Phosphofructokinase and pyruvate kinase have the highest flux control coefficients [7]. The nis gene cluster encodes nisin biosynthesis in L. lactis. It produces a 34-amino-acid lantibiotic. This lantibiotic disrupts bacterial cell wall synthesis. It binds lipid II, forms pores, and blocks peptidoglycan synthesis [6]. For recombinant therapeutic delivery, researchers have engineered L. lactis to secrete biologically active proteins. The most notable are trefoil factors and human IL-10. The nisin-controlled expression (NICE) system drives this. It allows tightly regulated, food-grade induction of transgene expression [4,5]. An enteric-coated formulation of recombinant L. lactis delivers live bacteria to the ileal mucosa. There, local secretion of IL-10 tunes the immune system without systemic exposure [4]. L. lactis is generally recognized as safe (GRAS). This is due to its long history of use in dairy fermentation and the absence of virulence determinants [1,3].
Health Benefits
L. lactis IL-1403 and MG1363 are not commercial probiotics in the conventional sense. Their primary health relevance is as genetically tractable chassis for mucosal delivery of bioactive therapeutics [4,5]. In a mouse model of colitis, L. lactis engineered to secrete trefoil factors (TFF) prevented and healed acute intestinal inflammation. This demonstrated proof-of-concept for recombinant live biotherapeutics [5] (animal model). An enteric-coated formulation of freeze-dried L. lactis producing human IL-10 was developed for ileal delivery. It was intended for inflammatory bowel disease. Clinical translation remains limited [4] (in vitro/formulation development). Nisin is produced by L. lactis subsp. lactis strains. It shows antimicrobial activity against Gram-positive pathogens. These include Listeria monocytogenes, Clostridium botulinum, and Staphylococcus aureus. Over 50 countries approve nisin as a food biopreservative [6] (in vitro/regulatory). The genome sequences of IL-1403 and MG1363 provided the foundation for understanding lactococcal metabolism, resistance to bacteriophage (a virus that infects bacteria), and stress response [1,2,3] (genomics). No human RCTs using L. lactis IL-1403 or MG1363 as a probiotic supplement have been published.
Biology
Lactococcus lactis is a Gram-positive, non-spore-forming, non-motile coccus. It is typically ovoid and occurs in pairs or short chains. It belongs to the Streptococcaceae family within the phylum Bacillota [1,3]. Two subspecies are distinguished. These are subsp. lactis (including IL-1403) and subsp. cremoris (including MG1363). They differ in metabolic and phenotypic traits. These include citrate utilization, maltose fermentation, and growth at 40°C [1,3]. L. lactis is mesophilic (optimal growth 30°C). It grows with or without oxygen. Its metabolism produces only lactic acid from sugar, yielding L-lactate from hexose fermentation [7]. Its natural habitat is dairy and plant material. Its relationship to the mammalian gut is transient [1]. The IL-1403 genome (2.365 Mb, no plasmids in the reference) encodes approximately 2,310 predicted proteins. It has a very low prophage load compared to wild-type strains [1,2,3].
Bibliography
Bolotin A, Wincker P, Mauger S, et al. (2001). The complete genome sequence of the lactic acid bacterium Lactococcus lactis ssp. lactis IL1403. Genome Research. 11(5):731-753. PMID: 11337471
Wegmann U, O’Connell-Motherway M, Zomer A, et al. (2007). Complete genome sequence of the prototype lactic acid bacterium Lactococcus lactis subsp. cremoris MG1363. Journal of Bacteriology. 189(8):3256-3270. PMID: 17307855
Le Bourgeois P, Lautier M, Van den Berghe L, et al. (1995). Physical and genetic maps of the chromosome of the Lactococcus lactis subsp. lactis strain IL1403 and Lactococcus lactis subsp. cremoris strain MG1363. Developments in Biological Standardization. 85:597-603. PMID: 8586238
Huyghebaert N, Vermeire A, Neirynck S, et al. (2005). Development of an enteric-coated formulation containing freeze-dried, viable recombinant Lactococcus lactis for the ileal mucosal delivery of human interleukin-10. European Journal of Pharmaceutics and Biopharmaceutics. 60(3):349-359. PMID: 15927456
Vandenbroucke K, Hans W, Van Huysse J, et al. (2004). Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology. 127(2):502-513. PMID: 15300583
Wang X, Kang W, Li J, et al. (2025). Nisin: harnessing nature’s preservative for the future of food safety and beyond. Critical Reviews in Food Science and Nutrition. 65(34):9045-9070. PMID: 40531107
Koebmann BJ, Andersen HW, Solem C, et al. (2002). Experimental determination of control of glycolysis in Lactococcus lactis. Antonie Van Leeuwenhoek. 82(1-4):237-248. PMID: 12369190
Available Products
Global dairy production uses L. lactis strains as starter cultures in cheese and fermented milk production. Culture companies including Chr. Hansen (Denmark) and Danisco/DuPont (Denmark) supply them commercially [3]. Nisin (Nisaplin, Danisco) is marketed as a food-grade biopreservative derived from L. lactis fermentation [6]. Recombinant L. lactis strains for therapeutic cytokine delivery remain at the preclinical and formulation stage. They are not commercially available [4,5].