The metabolic pathway and safety of Nisin

I. Metabolic Pathway of Nisin

Nisin, a natural polypeptide antibiotic produced by Lactococcus lactis, follows a metabolic pathway analogous to the natural degradation of proteins, primarily metabolized in the body through the following mechanisms:

Enzymatic Degradation into Amino Acids

As a polypeptide composed of 34 amino acids, Nisin is recognized and hydrolyzed by gastrointestinal proteases (e.g., pepsin, trypsin) into amino acid fragments upon ingestion. These amino acids (e.g., alanine, lysine, cysteine) further enter the body's amino acid metabolic pool, reused for protein synthesis or decomposed for energy. This degradation process mirrors the digestion of dietary proteins, yielding no unique metabolic intermediates.

Decomposition by Intestinal Microbiota

Partial Nisin fragments undegraded by pepsin enter the intestine, where peptidases from intestinal flora further break them into smaller peptides or free amino acids. This microbial decomposition aligns with the natural peptide metabolism mechanism, constituting a normal nutrient metabolic pathway.

Lack of Accumulation or Special Metabolic Pathways

Due to its natural polypeptide structure and the human body's absence of specific metabolic enzymes for its modified groups (e.g., lanthionine), Nisin degradation products are common amino acids, neither accumulating in the body nor entering abnormal metabolic pathways. Studies show Nisin has a short half-life in the gastrointestinal tract, with most degraded into absorbable amino acids within hours.

II. Safety Evaluation of Nisin in Vivo

As a food preservative and bioactive substance, Nisin's safety has been validated by extensive toxicological research and long-term practice, evaluated from the following dimensions:

1. Toxicological Research Evidence

Acute Toxicity

Nisin exhibits extremely low acute toxicity, with an oral LD₅₀ (median lethal dose) >2500 mg/kg body weight in rats, classified as "practically non-toxic" (WHO toxicity criteria: LD₅₀ >2000 mg/kg indicates low/non-toxic).

Subchronic and Chronic Toxicity

Animal studies (e.g., 90-day rat feeding trials) show no organ damage (liver, kidney, hematopoietic system) even at long-term high doses (hundreds of mg/kg body weight), with a no-observed-adverse-effect level (NOAEL) ≥250 mg/kg·bw/day.

Genotoxicity and Carcinogenicity

Multiple in vitro (e.g., Ames test, chromosomal aberration assay) and in vivo (e.g., mouse micronucleus test) studies confirm Nisin lacks mutagenicity or genotoxicity. Long-term carcinogenicity research also finds no evidence of tumor induction.

2. Human Safety Validation

Dietary Exposure Assessment

As a food additive (e.g., preservative in dairy and meat products), Nisin intake is far below safety thresholds. The FAO/WHO Joint Expert Committee on Food Additives (JECFA) sets an acceptable daily intake (ADI) of 0–33,000 IU/kg body weight (≈10 mg/kg・bw), while ordinary 人群 (populations) typically consume <0.1 mg/kg・bw/day via diet, well below the ADI.

Impact on Intestinal Microbiota

Research shows normal-dose Nisin does not significantly affect the composition or diversity of human intestinal flora. Although inhibitory to some Gram-positive bacteria (e.g., Staphylococcus aureus, Listeria), its rapid gastrointestinal degradation minimally impacts symbiotic Gram-positive bacteria (e.g., Bifidobacterium, Lactobacillus), preserving microecological balance.

Allergy and Immunogenicity

As a natural polypeptide, Nisin's amino acid sequence shares no homology with human proteins. While its modified amino acids (e.g., lanthionine) theoretically pose a negligible allergenic risk, long-term clinical observations report no allergic reactions, confirming negligible immunogenicity.

3. International Regulatory Recognition

FDA and EFSA Certification: The U.S. FDA lists Nisin as "Generally Recognized As Safe" (GRAS), and the EU EFSA confirms its safety for food use.

Food Additive Standards: China's GB 2760-2024 permits Nisin in dairy and meat products at maximum levels of 0.2–0.5 g/kg, further ensuring safe application.

Nisin's metabolic pathway mirrors that of natural proteins, degraded into amino acids via enzymatic and microbial processes without toxic byproducts. Its safety is fully validated by toxicological tests, human exposure assessments, and long-term applications, establishing it as a highly efficient and safe bioactive substance. This makes Nisin widely applicable in food preservation, functional foods, and potential pharmaceutical fields.