The Application of Nisin in special medical purpose formula foods

Food for Special Medical Purposes (FSMP) is a precision nutritional food designed for populations with specific diseases or physiological disorders who cannot consume ordinary food. Its quality and safety are directly related to patients' recovery and life health. As a key link in FSMP production, preservation must simultaneously meet three core requirements: "no safety risks, no impact on nutritional efficacy, and adaptation to special physiological states." Nisin (lacticin), a natural antimicrobial peptide, exhibits advantages such as non-toxicity, targeted antibacterial spectrum, easy degradation, and good compatibility with nutrients, perfectly aligning with the rigorous standards of FSMP. This article systematically analyzes its application value and practical pathways from the aspects of FSMP preservation pain points, Nisin's adaptability mechanisms, specific application scenarios, and optimization strategies.

I. Preservation Pain Points of FSMP and Core Adaptability of Nisin

1. Unique Preservation Challenges of FSMP

Due to the particularity of consumers, complexity of nutritional formulas, and specificity of consumption scenarios, FSMP faces far greater preservation difficulties than ordinary food:

High-Nutrient Matrix Prone to Microbial Growth: FSMP is typically rich in proteins, carbohydrates, fats, vitamins, and minerals. To meet digestion and absorption needs, it often uses easily utilizable nutrients such as hydrolyzed proteins, short peptides, and monosaccharides, forming a "high-nutrient matrix" that facilitates rapid microbial proliferation. It is susceptible to contamination by pathogenic and spoilage bacteria such as Staphylococcus aureus, Listeria monocytogenes, and Bacillus spp.

Incomplete Sterilization Due to Mild Processing: To retain the biological activity of heat-sensitive nutrients (e.g., vitamins, bioactive peptides, probiotics), the thermal sterilization intensity of FSMP is usually lower than that of ordinary food (e.g., pasteurization, low-temperature sterilization). This results in the survival of some heat-resistant spoilage bacteria (e.g., Bacillus subtilis) and spores, increasing the risk of spoilage during shelf life.

Extremely Low Tolerance to Preservatives in Consumers: FSMP consumers are mostly critically ill patients, post-operative recovery populations, individuals with digestive disorders, and immunocompromised individuals. They have weakened liver and kidney functions and metabolic capacity, leading to insufficient metabolism of chemical preservatives such as sodium benzoate and potassium sorbate. Long-term intake may cause adverse reactions or even worsen conditions.

High Compatibility Requirements Between Nutrients and Preservatives: FSMP has precise and complex nutritional formulas. Preservatives must avoid interactions with proteins, amino acids, vitamins, and other components, not affect nutrient absorption and utilization, and not alter food texture and taste (e.g., liquid FSMP must maintain homogeneity to prevent precipitation and stratification).

2. Core Advantages of Nisin Adapting to FSMP

The natural properties and mechanism of action of Nisin make it an ideal choice for FSMP preservation, with core adaptability reflected in:

Ultimate Safety: As a GRAS (Generally Recognized as Safe) certified substance, Nisin is produced by lactic acid bacteria fermentation. After human ingestion, it can be rapidly degraded into amino acids by digestive proteases, with no residues or toxicity. It does not burden the fragile metabolic system of patients or cause intestinal flora disturbance. Its ADI (Acceptable Daily Intake) value is unrestricted, making it suitable for various special populations (including infants, the elderly, and critically ill patients).

Targeted Antibacterial Activity: It precisely acts on common Gram-positive pathogenic and spoilage bacteria in food (e.g., Staphylococcus aureus, Listeria monocytogenes, Clostridium botulinum, Bacillus subtilis), which are the main contaminants in FSMP. It does not inhibit probiotics (e.g., Bifidobacterium, lactic acid bacteria) that may be added to FSMP, ensuring intestinal microecological balance.

Thermal Stability and Process Compatibility: It exhibits excellent heat resistance in acidic to neutral pH environments (common FSMP pH range: 4.0~7.0), retaining more than 80% of its activity after sterilization at 121℃. It is compatible with FSMP thermal processing technologies and maintains good stability under refrigerated and room-temperature storage conditions, adapting to FSMP with different storage requirements.

No Nutritional Interference or Flavor Impact: Nisin contains no organic solvents or chemical impurities, and does not chemically react with nutrients such as proteins, peptides, and vitamins. It does not affect nutrient content or bioavailability. Additionally, it has no off-odor and does not alter the original flavor and texture of FSMP, meeting the sensitive taste requirements of patients.

Strong Synergism: It can act synergistically with organic acids, plant extracts, probiotics, and physical preservation technologies (vacuum packaging, modified atmosphere packaging) to broaden the antibacterial spectrum, enhance preservation effects, reduce the dosage of single preservatives, and further lower safety risks.

II. Application Scenarios of Nisin in Different Types of FSMP

FSMP can be divided into multiple categories based on consumers' disease types and physiological states. The application of Nisin must be precisely adapted to product characteristics and preservation needs:

1. FSMP for Protein Component/Amino Acid Metabolism Disorders (e.g., Phenylketonuria, Maple Syrup Urine Disease Formula Foods)

The core characteristics of such FSMP are precise control of specific amino acid content, use of low-protein or protein-free matrices, simple nutritional composition easily utilizable by microorganisms, and consumers mostly being infants or children with extremely high requirements for preservative safety.

Application Scheme: Add 50~100 IU/mL Nisin in the late processing stage (after sterilization), combined with vacuum packaging and refrigerated storage (4℃). This can effectively inhibit the growth of Staphylococcus aureus and Bacillus subtilis, extending the shelf life to 6~12 months.

Advantages: The non-toxicity and amino acid degradation characteristics of Nisin do not increase the amino acid metabolic burden of patients; it has good compatibility with low-protein matrices and does not cause protein precipitation or changes in nutrients.

Precautions: Control the product pH within 5.0~6.5 to avoid Nisin inactivation in strongly alkaline environments; ensure uniform dispersion during addition to prevent local high concentrations from affecting taste.

2. FSMP for Digestive and Absorptive Disorders (e.g., Short Peptide-Type, Amino Acid-Type Enteral Nutrition Preparations)

Such FSMP is in liquid or semi-liquid form, using easily absorbable components such as hydrolyzed proteins, short peptides, and monosaccharides. It has high water activity (Aw＞0.9), is susceptible to microbial contamination, and patients have weak digestive functions with strict requirements for food safety and texture.

Application Scheme: Add 80~150 IU/mL Nisin before aseptic filling, combined with the process of "low-temperature sterilization (72℃, 15 min) + aseptic filling". This can inhibit the proliferation of heat-resistant spore-forming bacteria and Listeria monocytogenes, extending the room-temperature shelf life from 3 months to 6~9 months. For enteral nutrition preparations containing probiotics, Nisin can be added before probiotic addition, or microencapsulated probiotics can be used synergistically with Nisin to avoid mutual interference.

Advantages: Nisin is uniformly dispersed in the liquid matrix, forming a continuous antibacterial environment to prevent microbial proliferation inside the food; it has no off-odor, does not change the viscosity of liquid food, and does not affect patients' swallowing and digestive absorption.

Precautions: Avoid simultaneous addition with high concentrations of metal ions (e.g., Ca²⁺, Mg²⁺) to prevent metal ions from binding to Nisin and reducing antibacterial activity; select high-purity Nisin preparations without milk sources to adapt to lactose-intolerant patients.

3. FSMP for Cancer Patients (e.g., High-Energy, High-Protein Formula Foods)

FSMP for cancer patients is rich in high-quality proteins, unsaturated fatty acids, vitamins, and immunoactive substances, with high nutritional density and susceptibility to pathogenic bacteria contamination. Meanwhile, cancer patients have low immunity and a much higher infection risk than ordinary people, requiring ultimate food safety.

Application Scheme: Add 100~200 IU/mL Nisin, synergized with 0.1% citric acid (lowering pH to enhance Nisin activity), combined with modified atmosphere packaging (60% CO₂ + 40% N₂). This can effectively inhibit pathogenic bacteria such as Staphylococcus aureus and Clostridium botulinum, extending the room-temperature shelf life to 12 months. For solid nutritional supplements for cancer patients (e.g., protein bars, meal replacement powders), add 80~120 IU/g Nisin to inhibit the growth of molds and spore-forming bacteria during storage.

Advantages: Nisin precisely inhibits pathogenic bacteria, reducing the infection risk for patients after consumption; it has good compatibility with immunoactive substances (e.g., lactoferrin, glutamine) and does not affect their immunomodulatory efficacy; it is non-toxic and does not increase the liver and kidney metabolic burden of cancer patients.

Precautions: Control the Nisin addition amount not to exceed the maximum limit specified in GB 2760 (300 IU/mL in dairy-based FSMP, 500 IU/g in solid FSMP); avoid simultaneous addition with strong oxidants (e.g., excessive vitamin C) to prevent Nisin oxidation and inactivation.

4. FSMP for Diabetic Patients (e.g., Low-Sugar, High-Dietary Fiber Formula Foods)

The core characteristics of such FSMP are low sugar, high dietary fiber, and low glycemic index. The addition of dietary fiber may alter the microbial growth environment of the food matrix, and patients often have metabolic disorders with low tolerance to chemical preservatives.

Application Scheme: Add 60~100 IU/mL Nisin during production, synergized with 0.05% tea polyphenols (a natural antioxidant to broaden the antibacterial spectrum). This can inhibit the growth of molds, yeasts, and Gram-positive bacteria, extending the shelf life to 9~12 months. For ready-to-eat FSMP for diabetics (e.g., porridge, noodles), add 80~120 IU/mL Nisin, combined with vacuum packaging and mild sterilization to avoid food stickiness and rancidity.

Advantages: Nisin does not affect the glycemic index of food or cause blood glucose fluctuations; it has good compatibility with dietary fiber and low-sugar matrices, not causing precipitation or flavor changes; its natural properties align with the "healthy diet" needs of diabetic patients.

Precautions: Dietary fiber may adsorb part of Nisin, so the addition amount should be appropriately increased to ensure antibacterial efficacy; control the product water activity below 0.85 to synergize with Nisin and enhance preservation effects.

5. FSMP for Kidney Disease Patients (e.g., Low-Protein, Low-Salt, Low-Potassium Formula Foods)

FSMP for kidney disease patients strictly controls the content of nutrients such as proteins, sodium, and potassium, with a relatively simple matrix and susceptibility to microbial contamination. Meanwhile, patients have impaired renal function and extremely poor metabolic capacity for preservatives, requiring complete avoidance of chemical preservatives.

Application Scheme: Adopt the combined scheme of "Nisin (50~80 IU/mL) + vacuum packaging + low-temperature storage (4℃)". This can effectively inhibit the growth of spoilage bacteria, extending the shelf life to 6~8 months. For powdered FSMP for kidney disease (e.g., low-protein meal replacement powder), add 50~80 IU/g Nisin to inhibit the proliferation of heat-resistant spore-forming bacteria during storage and prevent stratification and rancidity after reconstitution.

Advantages: Nisin contains no sodium, potassium, or proteins, not increasing the renal metabolic burden of kidney disease patients; its degradation products are amino acids, which can serve as trace nutritional supplements, aligning with the needs of low-protein formulas.

Precautions: Avoid Nisin preparations containing sodium and potassium, and select high-purity, salt-free formula products; ensure thorough mixing with raw materials during addition for uniform dispersion.

III. Optimization Strategies and Key Technologies for Nisin Application in FSMP

1. Construction of Synergistic Preservation Systems: Enhancing Antibacterial Efficacy and Applicability

Nisin has weak inhibitory effects on Gram-negative bacteria and requires high concentrations when used alone. Combined with the complex matrix characteristics of FSMP, synergistic preservation systems need to be constructed:

Nisin + Organic Acids Synergy: Citric acid, lactic acid, malic acid, etc., can lower the pH of FSMP, enhance the penetration of Nisin into bacterial cell membranes, and directly inhibit Gram-negative bacteria (e.g., Escherichia coli). For example, adding 0.08% citric acid + 100 IU/mL Nisin to enteral nutrition preparations improves the antibacterial effect by 50% compared to single Nisin use, without affecting product nutrients and taste.

Nisin + Plant Extracts Synergy: Natural substances such as tea polyphenols, rosemary extract, and ε-polylysine can broaden the antibacterial spectrum, synergizing with Nisin to inhibit molds, yeasts, and Gram-negative bacteria. For example, adding 80 IU/mL Nisin + 0.05% tea polyphenols to FSMP for cancer patients improves the mold inhibitory effect by 60% compared to single Nisin use, with additional antioxidant effects.

Nisin + Physical Preservation Technologies Synergy: Vacuum packaging and modified atmosphere packaging (MAP) can reduce oxygen content, delay microbial growth, and synergize with Nisin to extend the shelf life. For example, FSMP for kidney disease patients using vacuum packaging + 50 IU/mL Nisin + 4℃ refrigeration has a shelf life twice as long as ordinary refrigeration. For high-temperature sterilized FSMP, the process of "high-temperature short-time sterilization + Nisin assistance" can reduce sterilization intensity and retain more heat-sensitive nutrients.

2. Precise Dosage Control and Addition Method Optimization

Dosage Control Principles: Comprehensively determine Nisin dosage based on FSMP type, water activity, processing technology, and storage conditions, adhering to the core principle of "minimum effective dosage" to avoid excessive addition. Generally, the addition amount is 50~200 IU/mL for liquid FSMP (enteral nutrition preparations, liquid formulas) and 50~150 IU/g for solid FSMP (meal replacement powders, protein bars), strictly following GB 2760 National Food Safety Standard for the Use of Food Additives and relevant special standards for FSMP.

Addition Method Optimization:

Heat-Sensitive FSMP (containing probiotics, vitamin C, etc.): Add in the late processing stage (after sterilization, cooled to below 40℃) to avoid high-temperature inactivation of Nisin.

Liquid FSMP: Dissolve Nisin in a small amount of sterile water or sterile normal saline (adapted for kidney disease patients) and slowly add with stirring to ensure uniform dispersion and prevent local high concentrations.

Solid FSMP: Pre-mix Nisin with dry raw materials (e.g., maltodextrin, dietary fiber) uniformly before subsequent processing to prevent Nisin aggregation and ensure antibacterial efficacy.

FSMP Containing Protein Hydrolysates: Add Nisin after protein hydrolysis and before sterilization to avoid peptides in hydrolyzates competing with Nisin for binding sites.

3. Process Optimization Adapting to FSMP

pH Regulation: Nisin exhibits optimal stability and antibacterial activity within the pH range of 4.0~6.5. During FSMP processing, the product pH should be controlled within this range, avoiding excessive addition of alkaline raw materials (e.g., sodium bicarbonate). If pH adjustment is required, organic acids such as citric acid and lactic acid are preferred.

Water Activity Control: Combining Nisin with water activity control (Aw＜0.85) can significantly enhance preservation effects and reduce Nisin dosage. For example, controlling the water activity of powdered FSMP below 0.6, combined with 50 IU/g Nisin, ensures no spoilage during 12 months of room-temperature storage.

Avoidance of Interfering Factors: High concentrations of metal ions such as Ca²⁺ and Mg²⁺ may bind to Nisin, reducing its antibacterial activity. If mineral supplements are added to FSMP, the metal ion concentration should be controlled, or chelated minerals (e.g., calcium citrate, magnesium lactate) should be selected to minimize interference with Nisin. Avoid simultaneous addition with strongly alkaline substances and strong oxidants to prevent Nisin degradation and inactivation.

IV. Application Precautions and Compliance Requirements

1. Safety and Applicability Verification

Adaptability to Special Populations: Nisin is suitable for most special populations (cancer patients, kidney disease patients, diabetic patients, infants). However, for patients allergic to milk, attention should be paid to potential milk-derived impurities in some Nisin preparations; high-purity Nisin products without milk sources and allergens should be selected.

Microbial Compatibility Verification: If probiotics are added to FSMP, experiments should be conducted to verify the impact of Nisin on probiotic activity. Methods such as microencapsulation of probiotics, adjusting the addition order (adding Nisin first, then probiotics), and controlling Nisin concentration can be used to ensure probiotic activity during shelf life.

Nutrient Compatibility Verification: Verify the compatibility of Nisin with nutrients such as proteins, peptides, vitamins, and minerals using methods such as high-performance liquid chromatography (HPLC) and gas chromatography (GC) to ensure nutrient content and bioavailability are not affected.

2. Compliance and Labeling Requirements

Standard Compliance: Strictly follow laws and standards such as the Food Safety Law of the People's Republic of China, General Standard for Food for Special Medical Purposes (GB 29922), and National Food Safety Standard for the Use of Food Additives (GB 2760). The addition amount and scope of Nisin must comply with regulations, and no off-label or excessive use is allowed.

Labeling Requirements: Clearly mark "Nisin (Lacticin)" on FSMP packaging labels, indicating its function as a "preservative," while meeting "clean label" requirements for patients and their families to understand. For FSMP dedicated to special populations, information such as "no chemical preservatives" and "natural preservation" should be indicated on labels to enhance consumer trust.

Testing and Quality Control: Establish detection methods for Nisin content (e.g., HPLC, microbial assay) to ensure product Nisin content meets formula requirements; strengthen microbial indicator testing (e.g., total viable count, pathogenic bacteria) to ensure product quality and safety during shelf life.

V. Industrialization Prospects and Future Development Directions

1. Industrialization Application Prospects

Meeting Safety Demands: The naturalness and non-toxicity of Nisin perfectly align with the ultimate safety requirements of FSMP for preservatives. It can replace chemical preservatives, reduce consumption risks for special populations, and provide guarantee for FSMP quality and safety.

Enhancing Product Competitiveness: The application of Nisin can promote the upgrading of FSMP towards "natural, healthy, and clean label," aligning with consumers' high-quality requirements for special medical food and enhancing product market competitiveness.

Reducing Production Costs: By extending the shelf life of FSMP by 30%~100%, it reduces losses during production, transportation, and storage; at the same time, it lowers sterilization intensity, saves energy costs, and improves enterprise economic benefits.

Broadening Application Scope: It can be adapted to various types of FSMP (digestive and absorptive disorders, cancer-specific, kidney disease-specific, diabetes-specific, etc.) with a wide range of application scenarios and great industrialization potential.

2. Future Development Directions

(1) Development of High-Purity, Customized Nisin Preparations

Develop high-purity Nisin preparations without milk sources, allergens, salt, and low potassium, adapting to FSMP for special populations such as milk-allergic, kidney disease, and hypertensive patients.

Target the characteristics of different types of FSMP (e.g., pH, water activity, nutrient composition), develop customized composite preservatives (e.g., special formulas of Nisin + organic acids + plant extracts), improving application convenience and effects.

(2) R&D of Sustained-Release and Targeted Nisin Preparations

Use microencapsulation, nanocarriers, liposomes, and other technologies to prepare sustained-release Nisin preparations, controlling the release rate of Nisin in FSMP to achieve long-term preservation and reduce addition amount.

Develop targeted Nisin preparations that release activity only under specific conditions (e.g., intestinal environment), avoiding impacts on probiotics in FSMP while enhancing inhibitory effects on intestinal pathogenic bacteria.

(3) Deepening Mechanism Research and Expanding Applications

Conduct in-depth research on the antibacterial mechanism of Nisin in complex nutritional matrices of FSMP, clarify its interactions with proteins, peptides, vitamins, and other components, and optimize application schemes.

Explore the synergistic effects of Nisin with functional ingredients such as immunoactive substances, probiotics, and dietary fiber, developing FSMP with both preservation and adjuvant therapeutic effects to enhance product added value.

(4) Standardization and Regulation Construction

Establish standardized process parameters, detection methods, and quality control systems for Nisin application in FSMP to ensure product quality stability and safety.

Strengthen industry exchanges and consumer education, popularize the natural properties and safety of Nisin, promote its wide application in FSMP, and foster the healthy development of the FSMP industry.

As a natural antimicrobial peptide, Nisin has irreplaceable value in the preservation of FSMP due to its core advantages of high safety, targeted antibacterial activity, and no nutritional interference. By precisely inhibiting Gram-positive pathogenic and spoilage bacteria, combined with synergistic preservation strategies, it can effectively address the pain points of FSMP such as high nutritional density, mild processing, and easy spoilage, while meeting the rigorous requirements of special populations for food safety and nutritional efficacy. Currently, Nisin has shown good application effects in various types of FSMP, but there is still room for improvement in the development of customized preparations, application of sustained-release technologies, and research on mechanisms in complex systems. With the rapid development of the FSMP industry and the continuous improvement of consumer requirements for product quality, Nisin is expected to become a core natural preservative for FSMP, promoting the development of the FSMP industry towards safety, health, and precision nutrition, and providing important guarantee for the dietary safety and recovery of special populations.