The allergic risk of Nisin

I. Allergenicity Assessment of Nisin

The allergenicity assessment of Nisin (nisin) requires comprehensive analysis of its chemical structure, immunogenic mechanism, and actual exposure risk:

1. Structural Basis and Immunogenic Potential

Polypeptide Properties and Epitope Characteristics

Nisin is a polypeptide composed of 34 amino acids, containing non-natural modified amino acids such as lanthionine and β-methyllanthionine, with no homology to human proteins. Allergens typically require specific linear or conformational epitopes (such as continuous amino acid sequences or glycosylation sites), but Nisin's modified structure makes it difficult to be recognized as a typical antigen by the human immune system.

Molecular Size and Degradation Characteristics

As a small polypeptide (molecular weight ~3.5 kDa), Nisin is much smaller than common allergens (e.g., ovalbumin ~45 kDa), usually unable to independently activate B cells to produce antibodies. Additionally, it is easily degraded into amino acid fragments by proteases in the gastrointestinal tract, further reducing the possibility of intact molecules triggering allergic reactions.

2. Experimental Evidence and Clinical Observations

In Vitro Allergy Model Validation

In vitro IgE binding assays show no significant binding between Nisin and specific IgE antibodies in allergic patients' serum; skin prick tests also reveal no positive reactions to Nisin in allergic populations. This indicates that Nisin is unlikely to induce allergies through IgE-mediated type I hypersensitivity mechanisms.

Human Exposure Data Support

As a food additive widely used for over 50 years, no clear Nisin-related allergic cases have been reported globally. Even in high-exposure groups (such as occupational contacts), no respiratory or skin allergic symptoms have emerged, further confirming its low allergenicity.

3. Cross-Reaction Risks with Other Proteins

Despite containing natural amino acids, Nisin has no cross-reactivity with common allergens (such as milk, egg, and soybean proteins) due to its unique sequence and modified structure. Studies show Nisin does not cross-bind with antibodies in food allergy patients' serum, so cross-reaction-induced allergy risks need not be worried about.

II. Potential Risk Analysis

Although Nisin is highly safe, the following potential risk scenarios and mechanisms require attention:

1. Non-Allergic Toxicity Risks

Intestinal Microbiota Disturbance from High-Dose Exposure

At doses far exceeding food additive levels (e.g., experimental high-dose intake), Nisin may inhibit intestinal Gram-positive commensal bacteria (such as Bifidobacterium and Lactobacillus), leading to short-term intestinal microecological imbalance. However, this effect is dose-dependent and almost nonexistent under normal dietary exposure (<0.1 mg/kg·bw/day).

Impact on Specific Populations

In theory, immunocompromised or intestinal barrier-damaged populations (such as critically ill patients) may have increased infection risks due to Nisin's weak inhibition of intestinal flora, but clinical evidence supporting this hypothesis is lacking.

2. Microbial Resistance Risks

Resistance Induction in Gram-Positive Bacteria

Nisin inhibits bacteria by damaging cell membranes, and long-term high-concentration use may induce resistance in Gram-positive pathogens (such as Staphylococcus aureus). However, in foods, Nisin's usage concentration (0.2–0.5 g/kg) is far below the resistance induction threshold, and combined use with other preservatives (such as organic acids) can reduce resistance risks.

Possibility of Horizontal Resistance Gene Transfer

Although Nisin resistance genes (such as nisI, nisR) naturally exist in Lactococcus lactis, these genes are located on plasmids, with extremely low probability of transferring to other pathogens, and Nisin resistance transmission has not been detected in clinical strains.

3. Impurity Risks in Production and Application

Safety of Fermentation By-Products

Nisin is produced by Lactococcus lactis fermentation, and fermentation broth may retain medium components (such as proteins, polysaccharides) or bacterial debris. Although purification processes remove most impurities, extremely rare sensitive individuals may have non-specific immune reactions to residual impurities, requiring risk reduction through quality control.

Unknown Effects of Chemical Modification or Degradation Products

Nisin may undergo structural modification (such as lanthionine ring opening) under extreme pH or high temperature, and the long-term safety of its degradation products is not fully clear. However, Nisin's usage conditions in food processing (pH 4–6, normal or low temperature) are mild, minimizing such issues.

III. Risk Prevention and Regulatory Measures

Dose Control: Strictly follow the FAO/WHO-recommended ADI value (0–10 mg/kg·bw), with maximum food usage ≤0.5 g/kg to ensure exposure far below risk thresholds.

Combined Use Strategy: Compound with other preservatives (such as lactic acid, citric acid) to reduce single-component dosage and minimize resistance induction risks.

Quality Standards: Control impurity content in Nisin products through purification processes, ensure purity >95%, and conduct batch safety testing.

Nisin's allergenicity is negligible, with potential risks mainly related to extreme dose exposure or production processes rather than the substance's inherent biological toxicity. Under standardized use, Nisin's safety as a natural preservative has been fully verified, with a risk-benefit ratio significantly superior to many chemically synthesized preservatives.