Sheep milk proteins and peptides: Nutritional value and health implications: A review

Sheep milk, containing approximately 5.8% protein, is primarily composed of casein (76-83%) and whey proteins (17-24%), making it an excellent source for investigating protein digestibility, metabolism, and the generation of bioactive compounds (Dalabasmaz et al., 2023) [17] . It is particularly recognized for its rich content of bioactive peptides that exhibit antioxidant, antihypertensive, antimicrobial, anti-inflammatory, and antidiabetic activities, highlighting its significant nutraceutical potential (Pipaliya et al., 2024; Flis et al., 2025) [26] . In addition to its healthpromoting properties, the high levels of protein, fat, and minerals in sheep milk contribute to improved cheese yield, better curd formation, and the development of innovative functional dairy products (Rako et al., 2019; Kayihura, 2023; Lai et al., 2024) [37] . Owing to its superior nutrient density and distinctive peptide composition compared with milk from other dairy species, sheep milk is increasingly considered a valuable resource for functional food research and product development (Wang et al., 2025) [63] . This review summarizes recent advances in the study of sheep milk proteins and peptides, highlighting their nutritional, functional, and industrial significance. Sheep milk contains approximately 5.8% protein, mainly consisting of casein (76-83%), including αs1-, αs2-, β-, and κ-caseins, along with 17-24% whey proteins, which together provide a well-balanced amino acid profile and may exhibit lower allergenicity because of reduced αs1-casein content (Zenk et al., 2024; Mohapatra et al., 2019) [65] . Bioactive peptides produced through enzymatic hydrolysis and fermentation demonstrate several health-promoting activities, including antioxidant, antihypertensive, antidiabetic, antimicrobial, and immunomodulatory effects. For example, the peptide HPHPHLSF derived from κ-casein has shown antioxidant activity comparable to BHT, while other peptides exhibit ACE-inhibitory activity for blood pressure regulation and DPP-IV inhibition for glycemic control. Peptidomic studies of fermented products such as kefir have also identified numerous bioactive peptide sequences (Taibo Li et al., 2017; Singh & Gaur, 2024; Nielsen et al., 2024) [51,60] . In addition, the high total solids content of sheep milk improves cheese yield and curd quality, supporting its use in the development of functional dairy products, including sheep milk-based ice cream enriched with whey proteins, inulin, omega-3 fatty acids, and probiotics (Kayihura, 2023; Kowalczyk et al., 2021) [37,41] . Despite these promising findings, further research is required to better understand peptide stability, bioavailability, and clinical efficacy, as well as to expand their applications in functional foods and biomedical fields such as wound healing and controlled-release delivery systems (Albenzio et al., 2017; Nizam et al., 2025; Al Shaer et al., 2024) [3,4,52] .

Composition of sheep milk proteins

Sheep milk possesses a significantly richer macronutrient profile than milk from most other dairy species, particularly in terms of protein content. It contains approximately 5.5-6.36% protein, which is considerably higher than the levels reported in cow, goat, buffalo, and camel milk (Arrichiello et al., 2022; Felice et al., 2021) [11,24] . Around 80% of the protein fraction in sheep milk consists of caseins, a proportion similar to bovine milk but higher than that found in human or mare milk (Flis et al., 2025) [26] . All major casein fractions, including αs1-, αs2-, β-, and κ-casein, are present, with total casein content ranging from 63-85% of total protein depending on breed variations. Among these fractions, α-caseins constitute about 23-35%, β-casein 6-12%, and κ-casein 7-9% (Alibekov et al., 2025) [6] . The remaining protein fraction is composed of whey proteins, primarily β-lactoglobulin, which accounts for nearly 22-24% of total protein and is important for binding hydrophobic compounds. α-lactalbumin contributes around 7-15% and provides essential amino acids along with immunomodulatory properties. Other whey proteins, such as serum albumin, lactoferrin, and immunoglobulins, are present in smaller quantities but play important antimicrobial and immune-supportive roles (Pillai et al., 2024; Figueroa Pires et al., 2021) [25,53] . This balanced composition of casein and whey proteins, together with the overall higher protein concentration, enhances the nutritional quality, cheese-making efficiency, and functional potential of sheep milk, making it a valuable dairy source for both nutritional and industrial applications (Salhi et al., 2025) [57] . [16] . In addition, microbial fermentation involving lactic acid bacteria such as Lactobacillus plantarum and Limosilactobacillus fermentum can produce multifunctional peptides with antioxidant, antimicrobial, antidiabetic, and anti-inflammatory activities (Prete et al., 2024) [54] . These findings demonstrate the important role of enzymatic and microbial processes in enhancing the therapeutic potential of sheep milk proteins through the production of bioactive peptides. Bioactive peptides derived from sheep milk exhibit a broad range of biological functions that contribute significantly to human health. Among the most studied are antihypertensive peptides, particularly those with angiotensin-converting enzyme (ACE) inhibitory activity, which are important for blood pressure regulation. Hydrolysates obtained from κcasein have shown strong ACE-inhibitory effects, and fermentation of sheep milk with Lacticaseibacillus paracasei M11 has demonstrated substantial ACE inhibition along with the production of peptides possessing antidiabetic potential (Pipaliya et al., 2025). Antioxidant peptides are another important group, including the κcasein-derived peptide HPHPHLSF produced through Bacillus protease hydrolysis, which displays lipid peroxidation inhibitory activity comparable to the synthetic antioxidant BHT due to the presence of amino acids such as histidine and leucine (Ashokbhai et al., 2022) [12] . Sheep milk peptides also exhibit antimicrobial properties, with peptides derived from αs1-, αs2-, β-, and κ-caseins identified in fermented products such as sheep milk kefir. Well-known examples include isracidin and casocidin, which are effective against several foodborne pathogens (Dallas et al., 2015; Park & Nam, 2015) [18] . In addition, immunomodulatory peptides generated during fermentation can support immune regulation, while lactoferrin-derived fragments such as lactoferroxins are known to stimulate natural killer cell activity and enhance humoral immune responses (Baars et al., 2023; Kashung & Karuthapandian, 2025) [14,36] . Certain peptides also possess opioid-like properties, including casomorphins from α-and β-caseins and whey-derived lactorphins and serorphins, which may influence gut motility and neural signaling (Trompette et al., 2003) [61] . Overall, the multifunctional nature of sheep milkderived peptides highlights their potential application in functional foods, nutraceuticals, and therapeutic products. Sheep milk is recognized as an important source of multifunctional bioactive peptides, with both casein-and whey-derived peptides exhibiting a wide range of healthpromoting activities. MALDI-TOF-MS analyses have identified numerous bioactive sequences from α-, β-, and κcaseins, including peptides with antibacterial, antioxidant, anticancer, anticoagulant, immunomodulatory, opioid-like, and ACE-inhibitory properties (Balthazar et al., 2024) [15] . Whey proteins also contribute valuable bioactive peptides, such as antibacterial and antidiabetic sequences. Processing techniques, particularly enzymatic hydrolysis and microbial fermentation, further enhance peptide production and biological activity. For instance, hydrolysis of sheep cheese whey generated β-lactoglobulin-derived peptides with significant ACE-inhibitory activity, while fermentation with Lacticaseibacillus paracasei M11 produced peptides exhibiting strong ACE inhibition along with α-amylase, αglucosidase, and lipase inhibitory activities associated with antidiabetic potential (Das et al., 2025; Mudgil et al., 2024) [19, 48] . Similarly, fermentation using Lactobacillus plantarum yielded peptide fractions with pronounced antioxidant and antimicrobial effects (Yilmaz et al., 2022) [64] . Peptidomic investigations of sheep milk kefir have identified a large number of peptide sequences, including several unique bioactive candidates specific to sheep milk fermentation products (Izquierdo-González et al., 2019) [33] . In silico studies further support the potential of sheep milk proteins as precursors of ACE-and DPP-IV-inhibitory peptides with antihypertensive and antidiabetic activities (Iram et al., 2022) [32] . Overall, these findings demonstrate that sheep milk represents a valuable reservoir of bioactive peptides with promising applications in functional foods, nutraceuticals, and therapeutic products.

Nutritional value of sheep milk proteins

Sheep milk is recognized for its high protein concentration and superior amino acid composition, providing important nutritional advantages over other dairy milks. It contains up to 6.62 g of protein per 100 g, which is significantly higher than the protein levels commonly reported in cow and goat milk (Landi et al., 2021). In addition to its elevated protein content, sheep milk proteins exhibit improved digestibility and bioavailability. Animal studies have shown greater ileal absorption of essential amino acids such as leucine, lysine, and methionine when compared with cow milk (Shrestha et al., 2021) [59] . Human studies also indicate that consumption of sheep milk leads to a stronger postprandial increase in circulating branched-chain amino acids, including leucine, isoleucine, and valine, as well as other essential amino acids like lysine, methionine, and proline, relative to cow milk (Milan et al., 2020). These characteristics highlight the nutritional value of sheep milk as a rich and highly digestible protein source The superior digestibility and balanced amino acid profile of sheep milk contribute significantly to muscle growth, recovery, and satiety. A randomized controlled trial involving physically active individuals showed that sheep milk effectively supported recovery after exercise-induced muscle damage, producing results comparable to cow milk and highlighting its potential in tissue repair and regeneration (Ravenwood et al., 2024). In particular, the high leucine content of sheep milk plays an important role in stimulating muscle protein synthesis through activation of the mTOR signaling pathway, making sheep milk especially relevant for sports nutrition and post-exercise recovery applications (Drummond & Rasmussen, 2008) [21] . Quantitative amino acid analyses further demonstrate the nutritional richness of sheep milk, particularly in essential and sulphur-containing amino acids. Studies on Alto Casertano sheep milk have shown that essential amino acids constitute nearly 41% of the total amino acid content, while methionine and cysteine together contribute about 4% (Rafiq et al., 2015) [55] . In addition, the free amino acid fraction is notably rich in proline and leucine, which are important for anabolic functions, muscle metabolism, and overall metabolic regulation (Kulzhanova et al., 2024) [42] . These characteristics highlight the nutritional and functional importance of sheep milk proteins in supporting metabolic health, muscle maintenance, and improved dietary quality.

Health implications of sheep milk proteins and peptides:

Sheep milk and its bioactive compounds have gained attention for their potential role in promoting human health through metabolic regulation, immune support, and inflammation control. Bioactive proteins and peptides derived from sheep milk may assist in weight management and obesity prevention by influencing satiety and energy metabolism. Fermented sheep milk products enriched with these peptides have been reported to stimulate gut hormones such as GLP-1 and PYY, which enhance feelings of fullness and may contribute to body-weight regulation (Tingirikari et al., 2024). In addition, these peptides exhibit inhibitory effects against enzymes including DPP-IV, α-glucosidase, and α-amylase, thereby slowing carbohydrate digestion and improving postprandial blood glucose responses. Fermented products such as kefir have also demonstrated insulinotropic effects, although their efficacy depends on the starter cultures and fermentation conditions used (Kumawat et al., 2025) [40] . Sheep milk is further enriched with conjugated linoleic acid (CLA) and angiotensin-converting enzyme (ACE)-inhibitory peptides that may support lipid metabolism, reduce inflammation, and promote cardiovascular health, although additional clinical evidence is needed (Alhaj & Kanekanian, 2014) [5] . Beyond metabolic functions, sheep milk contains important immune-related components such as immunoglobulins and lactoferrin, a multifunctional protein known for its antibacterial, antiviral, iron-binding, and immunomodulatory activities. Lactoferrin and its derived fragments help strengthen host defense by preventing pathogen adhesion and regulating cytokine activity, thereby enhancing innate immunity (Eker et al., 2024) [22] . Peptidomic analyses of sheep milk and fermented products have also identified peptides with antiinflammatory and immunomodulatory properties, including the ability to suppress pro-inflammatory cytokines in experimental studies (Joshi et al., 2025) [34] . Collectively, these findings suggest that sheep milk may serve as a valuable natural source of dietary immunomodulators and functional bioactive compounds, although further human studies are necessary to confirm their clinical benefits (Azizi et al., 2021) [13] . Sheep milk and its fermented products provide several advantages for gut and digestive health due to their effects on microbiota balance, digestibility, and lactose metabolism. Fermented products such as kefir and yogurt contain probiotic microorganisms and bioactive peptides that can positively influence gut microbiota composition, promote the formation of beneficial metabolites, and stimulate incretin release, thereby supporting digestive and metabolic health (Ahmad, Zhu, Chu, Danni, et al., 2025) [1] . Sheep milk also possesses distinct proteolytic and peptide characteristics compared with cow milk, which may contribute to improved digestibility and fewer intolerancerelated symptoms in some individuals who avoid cow milk. However, it still contains lactose and may trigger reactions in people with true bovine milk protein allergy (Nguyen et al., 2020) [50] . Fermentation further enhances tolerability by reducing lactose content and producing metabolites that support digestion, making fermented sheep milk beverages potentially suitable for lactose-sensitive consumers (Meena et al., 2025) [46] . The effectiveness of these benefits is influenced by factors such as the starter cultures used and the processing and storage conditions applied during production (Alm, 1982) [7] . Sheep milk and its bioactive compounds may also support cognitive, neurological, antimicrobial, and antioxidant functions. Proline-rich polypeptides (PRPs) and lactoferrinderived fragments obtained from sheep colostrum have demonstrated neuroprotective, anti-amyloidogenic, and antioxidant activities in preclinical studies, while some human studies have reported improvements in short-term memory and attention in older adults. However, larger and well-controlled clinical trials are still required to confirm these effects (Hong et al., 2024) [30] . Mechanistic evidence suggests that the antioxidative and immunomodulatory properties of these compounds may contribute to brain development and cognitive health, although further research is needed to establish their safe and effective dietary use (Nagai et al., 2019) [49] . Sheep milk also contains antimicrobial peptides effective against several foodborne pathogens, including E. coli, Salmonella typhimurium, Bacillus cereus, and Enterococcus faecalis, indicating their potential applications in food preservation and therapeutic interventions (Ván et al., 2006). In addition, antioxidant peptides derived from κ-casein have shown strong free radical-scavenging and lipid peroxidation inhibitory activities, in some cases comparable to synthetic antioxidants, highlighting their potential for reducing oxidative stress when incorporated into functional foods or stable bioactive formulations (Gómez-Ruiz et al., 2008) [28] .

Technological and industrial applications

Sheep milk-based products such as yogurt, cheese, and kefir are considered effective carriers of bioactive peptides generated during fermentation and storage (Kumawat et al., 2026) [37] . Peptidomic studies of sheep milk kefir have identified a large number of peptide sequences, including several with potential bioactive properties unique to sheep milk, with peptide concentration increasing as fermentation progresses, highlighting kefir as a rich source of functional peptides (Amorim et al., 2019) [9] . Specific starter cultures can further enhance these functional properties (Meena et al.2022) [47] . For example, fermentation with Lacticaseibacillus paracasei M11 has been associated with strong ACE-inhibitory and antidiabetic activities through inhibition of α-amylase, α-glucosidase, and lipase enzymes, while Limosilactobacillus fermentum KGL4 has demonstrated similar metabolic enzyme inhibitory effects, with peak bioactivity observed after approximately 48 hours of fermentation (Deveci et al., 2023) [20] . These findings emphasize the importance of selecting suitable starter cultures and fermentation conditions for industrial applications. Milk-derived peptides are increasingly recognized for their multifunctional properties, including antihypertensive, antidiabetic, antioxidant, antimicrobial, and mineral-binding activities, making them valuable ingredients for functional foods, nutraceutical formulations, and natural food preservatives. Their production can be optimized through techniques such as enzymatic hydrolysis, controlled fermentation, membrane separation, and mild processing methods that help preserve peptide bioactivity (Kashung & Karuthapandian, 2025) [36] . Studies have also shown that cardioprotective peptides derived from fermented milk can retain ACE-inhibitory activity after absorption, supporting their bioavailability and therapeutic potential (Zambrano-Cervantes et al., 2025). In addition, advanced processing approaches such as ultrasound-assisted fermentation have been reported to enhance peptide release while simultaneously improving texture and sensory quality, thereby increasing the value of premium sheep milk products (Gholamhosseinpour et al., 2025) [27] . Sheep milk possesses considerable potential for use in medical nutrition formulations because of its high protein content and good digestibility. Products enriched with sheep milk-derived bioactive peptides may provide metabolic benefits through ACE-inhibitory, DPP-IV-inhibitory, and glucosidase-inhibitory activities, while fermented lowlactose formulations may support immune function and gut health. Preliminary translational studies have indicated opportunities for developing specialized products such as ready-to-drink clinical nutrition beverages, high-protein gels, and peptide-based modular supplements designed for specific patient requirements. Nevertheless, successful application in the medical nutrition sector will require standardized methods for peptide analysis, improved understanding of gastrointestinal stability and bioavailability, and well-designed human clinical studies to validate efficacy and support health-related claims (Amigo & Hernández-Ledesma, 2020) [8] . [35] . Although recent developments in proteomics, including integrated LC-MS/MS, MALDI-TOF, and chemometric approaches, have enhanced peptide detection and profiling, validation across different breeds, geographical regions, and sample types remains limited (Rysova et al., 2022) [56] . Therefore, establishing standardized protocols for sample preparation, enzymatic digestion, and database utilization is essential to improve biomarker discovery, strengthen inter-study consistency, and support future regulatory acceptance of sheep milk-derived bioactive peptides (Punia et al., 2020). The bioavailability and stability of sheep milk-derived peptides remain important challenges for their successful application in functional foods and therapeutic products. Many bioactive peptides are vulnerable to degradation during gastrointestinal digestion, which can reduce their biological effectiveness (Mudgil, Ajayi, et al., 2024) [48] . However, in silico and in vitro digestion studies have shown that certain peptides, especially those containing high levels of proline residues, demonstrate greater resistance to enzymatic breakdown and are able to maintain their biological activity after digestion (Li et al., 2025) [44] . To identify peptides with the highest functional potential, researchers increasingly employ ADME profiling and computational platforms such as BIOPEP-UWM to predict absorption, distribution, metabolism, excretion, and nutraceutical properties. Despite these advances, further well-designed in vivo studies are necessary to validate the predicted stability, bioactivity, and clinical significance of these peptides (Kęska et al., 2021) [38] . Regulatory approval of functional foods containing sheep milk-derived peptides requires clear evidence of safety, efficacy, and consistent quality in accordance with standards established by authorities such as the EFSA and FDA (Luparelli et al). The approval of health claims depends on the availability of standardized analytical techniques and clinically validated results, which can slow the commercialization of new products (Lee et al., 2025) [43] . Regulatory evaluation also includes requirements related to accurate labeling, allergenicity assessment, and doseresponse validation, especially in the case of novel peptides and specialized functional formulations (Elsayed et al., 2025) [23] . Future research on sheep milk-derived peptides is expected to focus on strengthening clinical evidence, developing personalized nutrition strategies, promoting sustainable production systems, and advancing innovative peptide discovery. Well-designed human clinical trials are required to better understand the effects of these peptides on cardiometabolic health, satiety, immune regulation, and allergy management (Ahmad et al., 2025) [1] . Personalized nutrition approaches based on individual genetic, microbiome, and metabolic profiles may further enhance the targeted use of sheep milk peptides, although substantial foundational research is still needed in this area (Sarfraz et al., 2022) [58] . In parallel, sustainable sheep farming practices, including selective breeding for desirable milk protein characteristics and evaluation of environmental impacts, are essential for the ethical and large-scale production of functional sheep milk products (Sathika et al).

Additionally, the integration of high-throughput peptidomics with machine learning technologies is accelerating the identification and design of bioactive peptides with specific health benefits and improved potential for regulatory approval (Madsen et al., 2022) [45] .

Conclusion

Sheep milk proteins and bioactive peptides constitute an important source of nutritional and functional compounds, offering advantages over many other dairy species due to their high protein content, bioactive properties, and technological applications. The rich casein and whey protein composition enhances digestibility and amino acid availability while serving as a precursor for peptides with multiple health-promoting activities, including antihypertensive, antioxidant, antimicrobial, antidiabetic, and immunomodulatory effects. Findings from in vitro, in silico, and animal studies, together with limited but encouraging human research, indicate that sheep milkderived peptides may contribute to metabolic health, immune support, gut function, and cognitive well-being. From an industrial perspective, the high solids content and favorable protein composition of sheep milk make it particularly suitable for the production of cheese, yogurt, kefir, and other functional dairy products. Ongoing advances in fermentation technology, enzymatic hydrolysis, and peptidomics are further expanding its applications in nutraceuticals, medical nutrition, and biomedical fields. Despite these developments, important challenges remain, including the need for standardized peptide extraction methods, improved understanding of gastrointestinal stability and bioavailability, and stronger clinical validation of health benefits. In addition, regulatory approval requires substantial evidence regarding safety and efficacy before health claims can be accepted. Future progress is expected through the integration of high-throughput omics technologies, machine learning, and precision nutrition approaches, which may accelerate the discovery and application of novel bioactive peptides. At the same time, sustainable sheep farming practices and environmentally efficient processing methods will be essential for long-term development. Together, these advancements position sheep milk as not only a traditional dairy product but also a valuable resource for next-generation functional foods and health-promoting biomaterials.

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