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Bioactive Milk Proteins and Human Health

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Proteins and Amino Acids".

Deadline for manuscript submissions: 25 September 2024 | Viewed by 24021

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Prof. Dr. Esben Skipper Sørensen

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Guest Editor

Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark
Interests: molecular nutrition; bioactive food proteins; milk proteins and peptides; posttranslational protein modification; protein–cell interaction

Special Issue Information

Dear Colleagues，

The purpose of this Special Issue on “Bioactive Milk Proteins and Human Health” is to explore the most up-to-date available evidence about the role of milk proteins and peptides in human health.

Evolution has optimized mammals’ milk to provide their offspring with the optimal nutritive solution. Milk contains components that provide the neonate with both the necessary caloric energy and the building blocks needed for growth and development. Furthermore, milk contains numerous bioactive components, which provide signals and activities beyond classical nutrition. The majority of these bioactive components are proteins and encrypted peptides released during digestive processes. For example, milk contain proteins and peptides that possess antimicrobial activities influence blood pressure and development of lifestyle disease and play roles in the development of the gut and immune system, to mention a few.

On this topic, you are invited to submit proposals for manuscripts that investigate both in broader terms and at the mechanistic and molecular level the role of bioactive milk proteins in human health.

Prof. Dr. Esben Skipper Sørensen
Guest Editor

Manuscript Submission Information

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Keywords

human milk protein
cow's milk protein
lactation
infant formula
brain development
gastrointestinal development and disorders
growth and body composition
protein uptake
immunology
intestinal integrity

Published Papers (12 papers)

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Research

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17 pages, 3735 KiB

Open AccessArticle

The Immunomodulatory Effects of A2 β-Casein on Immunosuppressed Mice by Regulating Immune Responses and the Gut Microbiota

by Xiao Li, Xingru Lu, Ming Liu, Yu Zhang, Yujun Jiang, Xinyan Yang and Chaoxin Man

Nutrients 2024, 16(4), 519; https://doi.org/10.3390/nu16040519 - 13 Feb 2024

Cited by 1 | Viewed by 942

Abstract

The aim of this study was to investigate the immunomodulatory effects of A2 β-casein (β-CN) in cyclophosphamide-induced immunosuppressed BALB/c mice. Experiments conducted in vitro revealed that A2 β-CN digestive products have potent immunostimulatory activities. Animal studies demonstrated that A2 β-CN improved the immunological organ index reduction trend caused by cyclophosphamide, reduced the pathological damage to the spleen tissue in immunosuppressed mice, increased the release of IL-17A, IgG, and IgA, and reduced the production of IL-4. By regulating the relative abundance of advantageous bacteria like Oscillospira, Lactobacillus, and Bifidobacteria and harmful bacteria like Coprococcus and Desulfovibrionaceae, A2 β-CN improved gut microbiota disorders in immunosuppressed mice. Moreover, A2 β-CN promoted the production of short-chain fatty acids and increased the diversity of the gut microbiota. Therefore, ingestion of A2 β-CN is beneficial to the host’s immune system and gut health. These findings provide insights for the future application of A2 β-CN-related dairy products. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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15 pages, 1882 KiB

Open AccessArticle

Macrophage-Immunomodulatory Actions of Bovine Whey Protein Isolate, Glycomacropeptide, and Their In Vitro and In Vivo Digests

by Wyatt Olsen, Ningjian Liang and David C. Dallas

Nutrients 2023, 15(23), 4942; https://doi.org/10.3390/nu15234942 - 28 Nov 2023

Viewed by 934

Abstract

Whey protein isolate (WPI) consists of an array of proteins and peptides obtained as a byproduct of the cheesemaking process. Research suggests that WPI, along with its peptides such as glycomacropeptide (GMP), possesses immunomodulatory properties. These properties hold potential for alleviating the adverse effects of inflammatory conditions such as inflammatory bowel disease. Although promising, the immunoregulatory properties of the digested forms of WPI and GMP—those most likely to interact with the gut immune system—remain under-investigated. To address this knowledge gap, the current study examined the effects of in vitro-digested WPI and GMP, in vivo-digested WPI, and undigested WPI and GMP on the secretion of pro-inflammatory cytokines (TNF-α and IL-1β) in lipopolysaccharide-stimulated macrophage-like cells. Our results indicate that digested WPI and GMP reduced the expression of TNF-α and IL-1β, two pro-inflammatory cytokines. Whole WPI had no effect on TNF-α but reduced IL-1β levels. In contrast, in vivo-digested WPI reduced TNF-α but increased IL-1β. Undigested GMP, on the other hand, increased the secretion of both cytokines. These results demonstrate that digestion greatly modifies the effects of WPI and GMP on macrophages and suggest that digested WPI and GMP could help mitigate gastrointestinal inflammation. Further clinical studies are necessary to determine the biological relevance of WPI and GMP digestion products within the gut and their capacity to influence gut inflammation. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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14 pages, 1725 KiB

Open AccessArticle

Evaluating the Potential of Casein Glycomacropeptide in Adult Irritable Bowel Syndrome Management: A Pilot Study

by Yunyao Qu, Si Hong Park and David C. Dallas

Nutrients 2023, 15(19), 4174; https://doi.org/10.3390/nu15194174 - 27 Sep 2023

Cited by 3 | Viewed by 1322

Abstract

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that affects 10–15% of the global population and presents symptoms such as abdominal discomfort, bloating and altered bowel habits. IBS is believed to be influenced by gut microbiota alterations and low-grade inflammation. Bovine kappa-casein glycomacropeptide (GMP), a bioactive dairy-derived peptide, possesses anti-adhesive, prebiotic and immunomodulatory properties that could potentially benefit IBS patients. This pilot study investigated the effects of daily supplementation with 30 g of GMP for three weeks on gut health in five people with IBS. We assessed alterations in gut microbiota composition, fecal and blood inflammatory makers, and gut-related symptoms before, during and after the GMP feeding period. The results revealed no changes in fecal microbiota, subtle effects on systemic and intestinal immune makers, and no changes in gut-related symptoms during and after the GMP supplementation. Further research is needed to assess the potential benefits of GMP in IBS patients, including the examination of dosage and form of GMP supplementation. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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22 pages, 6183 KiB

Open AccessArticle

Fingerprinting of Proteases, Protease Inhibitors and Indigenous Peptides in Human Milk

by Martin Nørmark Thesbjerg, Søren Drud-Heydary Nielsen, Ulrik Kræmer Sundekilde, Nina Aagaard Poulsen and Lotte Bach Larsen

Nutrients 2023, 15(19), 4169; https://doi.org/10.3390/nu15194169 - 27 Sep 2023

Cited by 2 | Viewed by 1382

Abstract

The presence of proteases and their resulting level of activity on human milk (HM) proteins may aid in the generation of indigenous peptides as part of a pre-digestion process, of which some have potential bioactivity for the infant. The present study investigated the relative abundance of indigenous peptides and their cleavage products in relation to the abundance of observed proteases and protease inhibitors. The proteomes and peptidomes in twelve HM samples, representing six donors at lactation months 1 and 3, were profiled. In the proteome, 39 proteases and 29 protease inhibitors were identified in 2/3 of the samples. Cathepsin D was found to be present in higher abundance in the proteome compared with plasmin, while peptides originating from plasmin cleavage were more abundant than peptides from cathepsin D cleavage. As both proteases are present as a system of pro- and active- forms, their activation indexes were calculated. Plasmin was more active in lactation month 3 than month 1, which correlated with the total relative abundance of the cleavage product ascribed to plasmin. By searching the identified indigenous peptides in the milk bioactive peptide database, 283 peptides were ascribed to 10 groups of bioactivities. Antimicrobial peptides were significantly more abundant in month 1 than month 3; this group comprised 103 peptides, originating from the β-CN C-terminal region. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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12 pages, 763 KiB

Open AccessArticle

Effects of Whey Protein Supplementation on Inflammatory Marker Concentrations in Older Adults

by Samuel Adler, Wyatt Olsen, Bryna Rackerby, Rachel Spencer and David C. Dallas

Nutrients 2023, 15(18), 4081; https://doi.org/10.3390/nu15184081 - 21 Sep 2023

Viewed by 3258

Abstract

Although whey protein isolate (WPI) has been shown to be immunomodulatory, its ability to modulate production of a broad array of inflammatory markers has not previously been investigated in healthy adults. We investigated the effects of daily supplementation with 35 g of WPI for 3 weeks on inflammatory marker concentrations in the blood serum and feces of 14 older adult subjects (mean age: 59). Serum was analyzed using a multiplex assay to quantify the cytokines IFN-γ, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A and TNF-α. Fecal samples were analyzed using an ELISA for the inflammatory markers calprotectin and lactoferrin. Our results yielded high inter-subject variability and a significant proportion of cytokine concentrations that were below our method’s limit of quantification. We observed decreases in serum IL-12p70 in the washout phase compared with baseline, as well as the washout stage for fecal lactoferrin relative to the intervention stage. Serum IL-13 was also significantly reduced during the intervention and washout stages. Our data suggest that whey protein supplementation did not significantly alter most inflammatory markers measured but can alter concentrations of some inflammatory markers in healthy older adults. However, our study power of 35% suggests the number of participants was too low to draw strong conclusions from our data. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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11 pages, 976 KiB

Open AccessArticle

Effects of Lactoferrin on Oral and Throat Conditions under Low Humidity Environments: A Randomized, Double-Blind, and Placebo-Controlled Crossover Trial

by Shutaro Kubo, Hirotsugu Oda, Miyuki Tanaka, Takashi Koikeda and Shinichi Tomita

Nutrients 2023, 15(18), 4033; https://doi.org/10.3390/nu15184033 - 18 Sep 2023

Viewed by 1234

Abstract

To evaluate the effects of a single ingestion of bovine lactoferrin (bLF) on oral and throat conditions under a low-humidity environment. A randomized, double-blind, 2-sequence, 2-treatment, and 2-period placebo-controlled crossover trial was conducted. Healthy adult subjects orally ingested bLF dissolved in water, or placebo water, followed by exposure to low humidity (20 °C, 20% relative humidity (RH)) for 2 h. The primary endpoint was subjective oral and throat discomfort assessed by a visual analog scale (VAS), which positively correlated with the discomfort. Secondary endpoints were unstimulated whole salivary flow rate (UWSFR) and salivary immunoglobulin A (IgA) secretion rate. Overall, 40 subjects were randomly assigned to two sequences (20 each) and 34 were analyzed. The VAS values for oral and throat discomfort in the bLF treatment were significantly lower than in the placebo treatment, whereas UWSFR and IgA secretion rates were comparable between the two treatments. Adverse drug reactions were not observed. Subjective oral and throat discomfort associated with low humidity is suppressed by a single ingestion of bLF. Our findings demonstrate the novel use of bLF in a clinical situation that leverages its unique characteristics. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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9 pages, 586 KiB

Open AccessArticle

Effects of Bovine Lactoferrin on the Maintenance of Respiratory and Systemic Physical Conditions in Healthy Adults—A Randomized, Double-Blind, Placebo-Controlled Trial

by Hirotsugu Oda, Shutaro Kubo, Asuka Tada, Takumi Yago, Chihiro Sugita, Hiroki Yoshida, Tatsunori Toida, Miyuki Tanaka and Masahiko Kurokawa

Nutrients 2023, 15(18), 3959; https://doi.org/10.3390/nu15183959 - 13 Sep 2023

Viewed by 1615

Abstract

Objectives: We investigated the effects of bovine lactoferrin (LF) on the maintenance of the respiratory and systemic physical conditions. Methods: A randomized, double-blind, placebo-controlled trial was conducted. Healthy adults at Kyushu University of Health and Welfare ingested a placebo or bovine LF (200 mg/day) for 12 weeks. The primary endpoints were the total respiratory and systemic symptom scores. The secondary endpoint was the activity of plasmacytoid dendritic cells (pDCs) in peripheral blood. Results: A total of 157 subjects were randomized (placebo, n = 79; LF, n = 78), of whom, 12 dropped out. The remaining 145 participants were included in the full analysis set (placebo group, n = 77; LF group, n = 68). The total scores for respiratory and systemic symptoms during the intervention were significantly lower in the LF group than in the placebo group. The expression of CD86 and HLA-DR on pDCs was significantly higher in the LF group than in the placebo group at week 12. Adverse events were comparable between the groups, and no adverse drug reactions were observed. Conclusions: These results suggest that orally ingested LF supports the normal immune system via maintaining pDC activity, and maintains respiratory and systemic physical conditions in healthy adults. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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12 pages, 1821 KiB

Open AccessArticle

Effects of Whey Protein Isolate on Body Composition, Muscle Mass, and Strength of Chronic Heart Failure Patients: A Randomized Clinical Trial

by Elisa M. dos Santos, Annie S. B. Moreira, Grazielle V. B. Huguenin, Eduardo Tibiriça and Andrea De Lorenzo

Nutrients 2023, 15(10), 2320; https://doi.org/10.3390/nu15102320 - 16 May 2023

Cited by 1 | Viewed by 3498

Abstract

Heart failure (HF) is associated with a reduction of skeletal muscle mass. Whey protein isolate (WPI) has been beneficial in increasing muscle mass and strength, in addition to improving body composition. The goal of this research was to evaluate the effect of WPI on the body composition, muscle mass, and strength of chronic HF patients. For this purpose, twenty-five patients of both genders with predominantly NYHA I functional class and a median age of 65.5 (60.5–71.0) years were used to conduct a randomized, single-blind, placebo-controlled clinical trial and received 30 g per day of WPI for 12 weeks. Anthropometric measurements, body composition analysis, and biochemical exams were performed at the beginning and end of the study. An increase in skeletal muscle mass was observed in the intervention group after 12 weeks. A reduction in waist circumference, body fat percentage, and an increase in skeletal muscle index was observed when compared to the placebo group. No significant effect on muscle strength was observed after 12 weeks of intervention. These data demonstrate that WPI consumption contributed to the increase of skeletal muscle mass, strength, and reduction of body fat in HF patients. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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12 pages, 296 KiB

Open AccessArticle

Comparison of 30 Cytokines in Human Breast Milk between 1989 and 2013 in Japan

by Tomoki Takahashi, Hiroshi M. Ueno, Fumiya Yamaide, Taiji Nakano, Yuki Shiko, Yohei Kawasaki, Chisako Mitsuishi and Naoki Shimojo

Nutrients 2023, 15(7), 1735; https://doi.org/10.3390/nu15071735 - 1 Apr 2023

Cited by 3 | Viewed by 2121

Abstract

Milk cytokines play a vital role in mucosal immunity during infancy by supporting immune development and functions. Although the maternal background characteristics influence milk cytokines, changes in cytokine levels across generations remain unclear. Colostrum (C, n = 48) and mature milk (MM, n = 49) samples were collected from lactating Japanese women in 1989 (2727 samples) and 2013 (1408 samples). Milk cytokines were comprehensively measured using a suspension array and immunosorbent assays. The positive rates and cytokine concentrations were compared between the two generations using logistic and multiple regression analyses. Twenty-eight cytokines tested positive in all sample groups (1989-C, 1989-MM, 2013-C, and 2013-MM). The median osteopontin (OPN) level was significantly higher in the 1989-C group than in the 2013-C group (318.1 vs. 137.5 μg/mL; p = 0.0016) but did not differ between the MM groups. The median TGF-β1 level was significantly lower in the 1989-MM group than in the 2013-MM group (1056.2 vs. 1330.8 pg/mL; p = 0.008) but did not differ between the C groups. Most cytokines were comparable between generations, except for potential variation in the C-OPN and TGF-β1 levels. Milk cytokine secretion may reflect temporal changes in maternal background characteristics; however, the results from the analysis of 30-year-old samples may have influenced the milk cytokine levels. Further studies are needed with a larger number of milk samples collected from the same individuals at multiple time points over a wide lactation period, with detailed data on the maternal and infant background characteristics and diets. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

11 pages, 1041 KiB

Open AccessFeature PaperArticle

The Effect of Human and Bovine Milk Osteopontin on Intestinal Caco-2 Cells: A Transcriptome Comparison

by Brian Christensen, Albert J. Buitenhuis, Lotte N. Jacobsen, Marie S. Ostenfeld and Esben S. Sørensen

Nutrients 2023, 15(5), 1166; https://doi.org/10.3390/nu15051166 - 25 Feb 2023

Cited by 3 | Viewed by 1837

Abstract

Osteopontin (OPN) is a multifunctional protein abundantly present in human milk, whereas the concentration is significantly lower in bovine milk. Human and bovine milk OPN are structurally similar and both proteins resist gastric digestion and reach the intestines in a bioactive form. Intervention studies have indicated the beneficial effects of supplementing infant formula with bovine milk OPN and several in vivo and in vitro studies have shown that bovine milk OPN positively influences intestinal development. To investigate the functional relationship, we compared the effect of simulated gastrointestinal digested human and bovine milk OPN on gene expression in Caco-2 cells. After incubation, total RNA was extracted and sequenced and transcripts were mapped to the human genome. Human and bovine milk OPN regulated the expression of 239 and 322 genes, respectively. A total of 131 genes were similarly regulated by the OPNs. As a control, a whey protein fraction with a high content of alpha-lactalbumin had a very limited transcriptional impact on the cells. Enrichment data analysis showed that biological processes related to the ubiquitin system, DNA binding, and genes associated with transcription and transcription control pathways were affected by the OPNs. Collectively, this study shows that human and bovine milk OPN have a significant and highly comparable effect on the intestinal transcriptome. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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Review

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22 pages, 1263 KiB

Open AccessReview

The Role of Bovine Kappa-Casein Glycomacropeptide in Modulating the Microbiome and Inflammatory Responses of Irritable Bowel Syndrome

by Yunyao Qu, Si Hong Park and David C. Dallas

Nutrients 2023, 15(18), 3991; https://doi.org/10.3390/nu15183991 - 15 Sep 2023

Cited by 4 | Viewed by 1810

Abstract

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder marked by chronic abdominal pain, bloating, and irregular bowel habits. Effective treatments are still actively sought. Kappa-casein glycomacropeptide (GMP), a milk-derived peptide, holds promise because it can modulate the gut microbiome, immune responses, gut motility, and barrier functions, as well as binding toxins. These properties align with the recognized pathophysiological aspects of IBS, including gut microbiota imbalances, immune system dysregulation, and altered gut barrier functions. This review delves into GMP’s role in regulating the gut microbiome, accentuating its influence on bacterial populations and its potential to promote beneficial bacteria while inhibiting pathogenic varieties. It further investigates the gut microbial shifts observed in IBS patients and contemplates GMP’s potential for restoring microbial equilibrium and overall gut health. The anti-inflammatory attributes of GMP, especially its impact on vital inflammatory markers and capacity to temper the low-grade inflammation present in IBS are also discussed. In addition, this review delves into current research on GMP’s effects on gut motility and barrier integrity and examines the changes in gut motility and barrier function observed in IBS sufferers. The overarching goal is to assess the potential clinical utility of GMP in IBS management. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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20 pages, 864 KiB

Open AccessReview

Milk Osteopontin and Human Health

by Esben S. Sørensen and Brian Christensen

Nutrients 2023, 15(11), 2423; https://doi.org/10.3390/nu15112423 - 23 May 2023

Cited by 4 | Viewed by 2985

Abstract

Osteopontin (OPN) is a multifunctional protein found in all vertebrates. OPN is expressed in many different cell types, and is consequently found in most tissues and physiological secretions. OPN is involved in a multitude of biological processes, such as activation and regulation of the immune system; biomineralization; tissue-transformative processes, including growth and development of the gut and brain; interaction with bacteria; and many more. OPN is found in the highest concentrations in milk, where it is believed to initiate and regulate developmental, immunological and physiological processes in infants who consume milk. Processes for the isolation of bovine OPN for use in infant formula have been developed, and in recent years, many studies have investigated the effects of the intake of milk OPN. The purpose of this article is to review and compare existing knowledge about the structure and function of milk OPN, with a particular focus on the effects of milk OPN on human health and disease. Full article

(This article belongs to the Special Issue Bioactive Milk Proteins and Human Health)

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