The antimicrobial metabolite nisin Z reduces intestinal tumorigenesis and modulates the cecal microbiome in ApcMin/+ mice.

UNLABELLED: Nisin Z, an antimicrobial metabolite produced by Lactococcus lactis spp., has been safely used as a food preservative for many years. Nisin Z also showed promising activity against various cancer types in vitro, and significantly reduced tumor size in an ectopic head and neck cancer model. Here, we investigate the activity of nisin Z for colorectal cancer treatment and observed an in vitro reduction in cellular proliferation, and a moderate enhancement in cell death. We next analyzed the effect of oral nisin Z administration in the Apcmin/+ intestinal adenoma mouse model. We measured tumor burden along the gastrointestinal tract and observed a decrease in tumor burden in the middle region of the small intestine, but not in the lower region or colon. Since tumor progression in the Apcmin/+ model is exacerbated by an inflammatory environment, we next determined whether nisin Z impacts this in a direct or indirect manner. We show that nisin Z can directly reduce NF-κB activation in a dose-dependent manner. In addition, nisin Z impacted the cecal microbiome composition as well as microbiota-associated plasma metabolites, causing an overall shift towards a more health-associated profile. Interestingly, the Apcmin/+ genotype differentially impacted the nisin Z-mediated differences in cecal microbiome composition and plasma metabolites compared to wildtype animals. In summary, our data suggest that the reduction in small intestinal tumor burden could be due to nisin Z's contribution to a reduced pro-inflammatory environment. Future studies will reveal whether nisin's localized effect is due to degradation of the peptidic compound in more distal regions of the gastrointestinal tract and focus on development of delivery systems to increase efficacy.

IMPORTANCE: With the increased incidence of colorectal cancer, especially among younger individuals, it is critical to study approaches that help with the prevention and treatment of this debilitating disease. Our study indicates that nisin Z, a bacterially produced peptide antibiotic, decreases the growth of colorectal cancer cells and moderately increases cell death in vitro. Oral administration of nisin Z in an intestinal adenoma mouse model revealed a reduction of tumor burden in the middle region of the small intestine. This decreased tumor burden might in part be attributed to a direct anti-inflammatory effect, as well as an indirect effect on the gut microbiota and their metabolites due to nisin Z's antibacterial activity. Overall, we demonstrate a potential activity for nisin Z in the prevention or amelioration of inflammation-associated colorectal cancer, underscoring the significance of investigating the properties of bacterial natural products in human health.