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The concept that extracellular vesicles (EVs) from the diet can be absorbed by the intestinal tract of the consuming organism, be bioavailable in various organs, and in-turn exert phenotypic changes is highly debatable. Here, we isolate EVs from both raw and commercial bovine milk and characterize them by electron microscopy, nanoparticle tracking analysis, western blotting, quantitative proteomics and small RNA sequencing analysis. Orally administered bovine milk-derived EVs survive the harsh degrading conditions of the gut, in mice, and is subsequently detected in multiple organs. Milk-derived EVs orally administered to mice implanted with colorectal and breast cancer cells reduce the primary tumor burden. Intriguingly, despite the reduction in primary tumor growth, milk-derived EVs accelerate metastasis in breast and pancreatic cancer mouse models. Proteomic and biochemical analysis reveal the induction of senescence and epithelial-to-mesenchymal transition in cancer cells upon treatment with milk-derived EVs. Timing of EV administration is critical as oral administration after resection of the primary tumor reverses the pro-metastatic effects of milk-derived EVs in breast cancer models. Taken together, our study provides context-based and opposing roles of milk-derived EVs as metastasis inducers and suppressors. Dietary extracellular vesicles (EVs) could potentially be absorbed by the intestinal tract of the host and exert multiple phenotypic changes. Here, the authors isolate and characterize EVs from raw and commercial bovine milk and show orally administered EVs to have a context specific role in promoting or suppressing primary tumor growth and metastasis in multiple mouse tumor models.

Despite our knowledge of the protective role of antibodies passed to infants through breast milk, our understanding of immunity transfer via maternal leukocytes is still limited. To emulate the immunological interface between the mother and her infant while breast-feeding, we used murine pups fostered after birth onto MHC-matched and MHC-mismatched dams. Overall, data revealed that: 1) Survival of breast milk leukocytes in suckling infants is possible, but not significant after the foster-nursing ceases; 2) Most breast milk lymphocytes establish themselves in specific areas of the intestine termed Peyer's patches (PPs); 3) While most leukocytes in the milk bolus were myeloid cells, the majority of breast milk leukocytes localized to PPs were T lymphocytes, and cytotoxic T cells (CTLs) in particular; 4) These CTLs exhibit high levels of the gut-homing molecules α4β7 and CCR9, but a reduced expression of the systemic homing marker CD62L; 5) Under the same activation conditions, transferred CD8 T cells through breast milk have a superior capacity to produce potent cytolytic and inflammatory mediators when compared to those generated by the breastfed infant. It is therefore possible that maternal CTLs found in breast milk are directed to the PPs to compensate for the immature adaptive immune system of the infant in order to protect it against constant oral infectious risks during the postnatal phase.

Bovine lactoferrin (LF) is mainly present in milk and shows important physiological and biological functions. The aim of this study was to estimate the heritability and correlation values of LF content in bovine milk with different economic traits as milk yield (MY), fat and protein percentages, and somatic cell score (SCS). Variance components of the studied traits were estimated by REML using a multiple-trait mixed model. The obtained heritability (0.22) for LF content predicted using mid-infrared spectrometry (pLF) suggested the possibility of animal selection based on the increase of LF content in milk. The phenotypic and genetic correlation values calculated between pLF and SCS were moderate (0.31 and 0.24, respectively). Furthermore, a preliminary study of bovine LF gene polymorphism effects was performed on the same production traits. By PCR, all exons of the LF gene were amplified and then sequenced. Three new polymorphisms were detected in exon 2, exon 11, and intron 8. We examined the effects of LF gene polymorphisms of exons 2, 4, 9, 11, and 15, and intron 8 on pLF, MY, fat and protein percentages, and SCS. The different observed effects did not reach a significant level probably because of the characteristics of the studied population. However, the results were promising, and LF may be a potential indicator of mastitis. Further studies are necessary to evaluate the effect of genetic selection based on LF content on the improvement of mastitis resistance.

Exosomes, the extracellular secretary nano-vesicles, act as carriers of biomolecules to the target cells. They exhibit several attributes of an efficient drug delivery system. Curcumin, despite having numerous bioactive and therapeutic properties, has limited pharmaceutical use due to its poor water solubility, stability, and low systemic bioavailability. Hence, this study aims to enhance the therapeutic potential of curcumin, a model hydrophobic drug, by its encapsulation into milk exosomes. In the present study, we investigated the stability of free curcumin and exosomal curcumin in PBS and in vitro digestive processes. Additionally, their uptake and trans-epithelial transport were studied on Caco-2 cells. Curcumin in milk exosomes had higher stability in PBS, sustained harsh digestive processes, and crossed the intestinal barrier than free curcumin. In conclusion, the encapsulation of curcumin into the exosomes enhances its stability, solubility, and bioavailability. Therefore, the present study demonstrated that milk exosomes act as stable oral drug delivery vehicles.

Mastitis is a multifactorial inflammatory disease. The increase in antibiotic resistance of bacteria that cause mastitis means that cattle breeders would prefer to reduce the use of antibiotics. Recently, therapies using mesenchymal stem cells (MSCs) from various sources have gained significant interest in the development of regenerative medicine in humans and animals, due to their extraordinary range of properties and functions. The aim of this study was to analyze the effectiveness of an allogeneic stem cells derived from bone marrow (BMSC) and adipose tissue (ADSC) in treating mastitis in dairy cattle. The research material consisted of milk and blood samples collected from 39 Polish Holstein-Friesian cows, 36 of which were classified as having mastitis, based on cytological evaluation of their milk. The experimental group was divided into subgroups according to the method of MSC administration: intravenous, intramammary, and intravenous + intramammary, and according to the allogeneic stem cells administered: BMSC and ADSC. The research material was collected at several time intervals: before the administration of stem cells, after 24 and 72 h, and after 7 days. Blood samples were collected to assess hematological parameters and the level of pro-inflammatory cytokines, while the milk samples were used for microbiological assessment and to determine the somatic cells count (SCC). The administration of allogeneic MSCs resulted in a reduction in the total number of bacterial cells, Staphylococcus aureus , bacteria from the Enterobacteriaceae group, and a systematic decrease in SCC in milk. The therapeutic effect was achieved via intravenous + intramammary or intramammary administration.

Buffalo milk is renowned for its nutritional and functional properties. Milk somatic cells protect the mammary gland, contribute to the functionality of the udder, and also aid in the health and development of newborn calves, particularly during the critical early lactation period. However, proteomic changes in buffalo milk somatic cells during the transition from colostrum to mature milk remain poorly understood. This study was formulated to characterize the proteomic dynamics of buffalo milk somatic cells using Liquid chromatography-tandem mass spectrometry (LC-MS/MS) during colostrum-to-mature milk transition and to reveal shifts in metabolic and immune functions. A total of 4,429 high-confidence proteins were identified in the colostrum and milk of buffaloes. Up-regulated proteins [P adj <0.05, log 2 (Fold change, FC) ≥ 1.5] across different days of sampling were involved in metabolism of sugars, lipids, and amino acids, pentose-phosphate pathway, insulin-signaling, biosynthesis of amino acids and cofactors, and ubiquitin-proteasome system. Down-regulated proteins [P adj <0.05, log 2 (FC) ≤ 0.5] were associated with lipid transport, aldosterone synthesis and secretion, mineral balance, complement-coagulation system, antigen processing and presentation, and mRNA processing. A notable shift in hub proteins was detected, and selected ones were validated by real-time qPCR. These findings highlight significant changes in the proteome profile, biological functions, and specific pathways in milk somatic cells during early lactation in buffaloes. In conclusion, milk somatic cells contribute not only to mammary immunity but also to the nutritional support of the growing calf.

Heat stress in dairy cattle leads to reduction in feed intake and milk production as well as the induction of many physiological stress responses. The genes implicated in the response to heat stress in vivo are not well characterised. With the aim of identifying such genes, an experiment was conducted to perform differential gene expression in peripheral white blood cells and milk somatic cells in vivo in 6 Holstein Friesian cows in thermoneutral conditions and in 6 Holstein Friesian cows exposed to a short-term moderate heat challenge. RNA sequences from peripheral white blood cells and milk somatic cells were used to quantify full transcriptome gene expression. Genes commonly differentially expressed (DE) in both the peripheral white blood cells and in milk somatic cells were associated with the cellular stress response, apoptosis, oxidative stress and glucose metabolism. Genes DE in peripheral white blood cells of cows exposed to the heat challenge compared to the thermoneutral control were related to inflammation, lipid metabolism, carbohydrate metabolism and the cardiovascular system. Genes DE in milk somatic cells compared to the thermoneutral control were involved in the response to stress, thermoregulation and vasodilation. These findings provide new insights into the cellular adaptations induced during the response to short term moderate heat stress in dairy cattle and identify potential candidate genes ( BDKRB1 and SNORA19 ) for future research.

Extracellular vesicles (EVs) are involved in cell-to-cell communication and modulation of numerous physiological and pathological processes. EVs are found in large quantities in milk and contain several inflammation- and immunity-modulating proteins and microRNAs, through which they exert beneficial effects in several inflammatory disease models. Here, we investigated the effects of two EV subsets, concentrated from commercial cow’s milk, on a murine model of colitis induced with dextran sodium sulfate (DSS). P35K EVs, isolated by ultracentrifugation at 35,000 g, and P100K EVs, isolated at 100,000 g, were previously characterized and administered by gavage to healthy and DSS-treated mice. P35K EVs and, to a lesser extent, P100K EVs improved several outcomes associated to DSS-induced colitis, modulated the gut microbiota, restored intestinal impermeability and replenished mucin secretion. Also, P35K EVs modulated innate immunity, while P100K EVs decreased inflammation through the downregulation of colitis-associated microRNAs, especially miR-125b, associated with a higher expression of the NFκB inhibitor TNFAIP3 (A20). These results suggest that different milk EV subsets may improve colitis outcomes through different, and possibly complementary, mechanisms. Further unveiling of these mechanisms might offer new opportunities for improving the life of patients with colitis and be of importance for milk processing, infant milk formulation and general public health.

High-lactation cows exhibit advantages in milk yield and quality compared to low-lactation cows; however, the underlying mechanisms remain unclear. Based on the demand for high-quality milk sources in the food industry, this study used single-cell sequencing technology (scRNA-seq) on the 10 × Chromium platform to analyze the milk cells of 10 Holstein cows (5 in the high-lactation group and 5 in the low-lactation group). The seven cell types included two types of epithelial cells (epithelial and secretory epithelial cells) and five types of immune cells (neutrophils, T cells, macrophages, B cells, and dendritic cells). Further sub-clustering analysis identified three epithelial cell types and nine T-cell subsets, and their differentiation paths were depicted through pseudo temporal analysis. Inter-group comparisons revealed differential genes and signaling pathways that affect lactation performance, such as lactation-related pathways (prolactin, protein export, thermogenesis) and immune-related pathways (Toll-like receptor, cytokine-receptor interaction, and NF-κB). In addition, this study elucidated the complex signaling relationships between epithelial and immune cells, especially the impact of CyPA, ICAM, and SELL signaling pathways on lactation. Moreover, additional analyses of macrophage and neutrophil subpopulations further revealed their interactions with epithelial cells, providing complementary insights into immune regulation during lactation.This study enriches the knowledge of cow lactation biology and provides a reference for the food industry to screen high-quality milk sources and optimize dairy processing technology.

No nationwide studies of the incidence rate of clinical mastitis (IRCM) have been conducted in Canada. Because the IRCM and distribution of mastitis-causing bacteria may show substantial geographic variation, the primary objective of this study was to determine regional pathogen-specific IRCM on Canadian dairy farms. Additionally, the association of pathogen-specific IRCM with bulk milk somatic cell count (BMSCC) and barn type were determined. In total, 106 dairy farms in 10 provinces of Canada participated in the study for a period of 1 yr. Participating producers recorded 3,149 cases of clinical mastitis. The most frequently isolated mastitis pathogens were Staphylococcus aureus, Escherichia coli, Streptococcus uberis, and coagulase-negative staphylococci. Overall mean and median IRCM were 23.0 and 16.7 cases per 100 cow-years in the selected herds, respectively, with a range from 0.7 to 97.4 per herd. No association between BMSCC and overall IRCM was found, but E. coli and culture-negative IRCM were highest and Staph. aureus IRCM was lowest in low and medium BMSCC herds. Staphylococcus aureus, Strep. uberis, and Streptococcus dysgalactiae IRCM were lowest in the Western provinces. Staphylococcus aureus and Strep. dysgalactiae IRCM were highest in Québec. Cows in tie-stalls had higher incidences of Staph. aureus, Strep. uberis, coagulase-negative staphylococci, and other streptococcal IRCM compared with those in free-stalls, whereas cows in free stalls had higher Klebsiella spp. and E. coli IRCM than those in tie-stall barns. The focus of mastitis prevention and control programs should differ between regions and should be tailored to farms based on housing type and BMSCC.