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Milk Genomics and Human Health: A Report from the 14th Symposium

Written by: Peter Williamson, Ph.D. | Issue # 67 | 2017

The 14th International Symposium on Milk Genomics and Human Health was held in the warm and welcoming surrounds of Quebec City, Canada. This was the first time the consortium has been held in Canada, and it was a great opportunity to experience the hospitality and learn from the wonderful dairy science culture of the Canadians and the international program that the committee had assembled.

The meeting opened with a retrospective on the 14 years of IMGC, with a personal perspective by Gerrit Hiddink. Gerrit was a founding scientist and illuminated the IMGC origins and the developments since its inception. The personal views from Gerrit reinforced what participants have come to expect and enjoy from the symposium, the multi-disciplinarity and tremendous breadth and depth of milk science and genomics. This expands the horizons of participants and challenges conventional views so everyone learns something new. This is at the core of the philosophy of the meeting and has become a sustaining driver of this symposium.

Danielle Lemay has been presenting updates on the metrics of the Symposium outcomes and participant outcomes for a number of years now. This year the presentation stepped up to another level with a deep analysis that demonstrated the astounding impact of the meeting on collaboration and quality research that is fostered by the symposium. Watch for the details of the analysis in future publications.

Danielle’s talk was followed by the first of our invited speakers, Filippo Miglior from the Canadian Dairy Network. Filippo presented the state-of-the-art in genome prediction and phenotyping in the national Canadian dairy cattle improvement program. Genome prediction is now a major contributor to herd improvement and has contributed accelerated gain in recent years. He made the point that the dairy genome project had returned an estimated 250x return on investment since 2009. The power of this applied genomics methodology and a cost-effective access has fostered the drive for more valued phenotype analysis. Filippo described the Canadian program’s efforts to capture in-depth analysis of milk composition from 750,000 samples. This tremendous resource will make milk a highly sophisticated natural product for decades into the future.

The next session covered aspects of lactation genomics. Monique Rijnkels has been leading a lactation annotation effort as part of the Functional Annotation of Animal Genomes global network. Monique and her colleagues have explored a detailed analysis of transcriptomes and genome modifications in an attempt to unravel the complexities of mammary gland function. This is a huge undertaking and continues to amaze the researchers in its complexity and technical challenges. The project will continue to develop the annotation to identify non-coding DNA in the bovine genome that contributes to the production of milk.

Nina Poulsen from the Danish-Swedish Dairy Genomics Initiative presented their latest analysis of milk oligosaccharides. They found a significant effect of parity and breed on the relative proportion of acidic, neutral and fucosylated oligosaccharides. Genome-wide association analysis identified a complex pattern of potential genomic regions driving this trait, and candidates are under further investigation. However, the heritability estimates do suggest that there is room to select for oligosaccharide composition.

Klaus Lehnert provided a genomics perspective on the small but emerging dairy goat industry in New Zealand. Klaus has genotyped representative animals from the primary industry-contributing farms in NZ and found an extremely structured goat population. A single chromosomal region characterized the selected animals, suggesting that farmers had established the industry on the basis of a very narrow genetic base. It will be interesting to see how the farmers engage with genetic selection strategies to develop the industry in coming years.

Rachel Gervais, an animal nutritionist from Univesité Laval, provided a detailed analysis of milk fatty acid profiles and the influence of feed composition and rumen microbiota. Lipid composition of milk has been re-evaluated in recent years, and there is a lot of interest in beneficial and bioactive properties of fatty acids. Rachel provided a detailed overview of the variation in milk lipid composition that is found in different production systems. The composition is not only relevant to consumers and processing but is an accurate biomarker of rumen function.

Darryl Hadsell continued on the theme of milk composition but in an entirely different context, consistent with the IMGC diverse systems approach. He showed a detailed genetic analysis of milk composition in the mouse diversity panel, highlighting a range of genome regions associated with milk components, and specific regions of interest that were potential causal candidate genes. However, as he pointed out, there was an apparent gap in the linkage between peak signals and key candidates in two primary associated regions, suggesting an apparent but unannotated functional association between gene and intergenic sequence. Nevertheless, there was clear evidence of concordance between 8/19 associated regions between the mouse model and those described in dairy cattle.

Alexandra Carrier from Université Laval provided an interesting insight into efforts to conserve the Canadienne breed of dairy cattle. This resilient breed was brought to Canada in the 19th century, and by 1850 there were an estimated 300,000 individuals on-farm. The numbers dropped in the 20th century as other breeds replaced dairy herds so that only 10,000 were left by 1970 and were crossed with Swiss Brown. Alexandra estimated the effective population size at around 43 and described the strategy to save the breed and its characteristic traits by increasing diversity and improving udder conformation.

The milk metabolome is now within reach of detailed analytical profiling using NMR. Ulrik Kræmer Sundekilde described the variation in milk metabolites in human milk. The study was focused on the comparison of pre-term milk and full-term milk at various stages of lactation. There were notable differences in oligosaccharide and branched amino acid composition. After approximately 5 weeks, the pre-term samples resembled full-term milk.

Kasper Hettinga has been interested in milk proteomics throughout his career in The Netherlands. This year he explored the variation in the proteome of cow’s milk at different stages of lactation and with varied diets. The most significant variation was between individual cows, with 50% of variation happening in proteins with immune or protease or protease inhibitor functions. There was a strong correlation between these  groups of proteins.

André Marette from INAF at Univesité Laval described a series of studies on the effects of milk products, especially fermented products, on metabolic and cardiovascular markers. His group was particularly interested in examining whether the products would influence the mice via changes to gut microbiota. He showed data to demonstrate some effect of fermented milk-derived peptide supplements on improving insulin sensitivity in LDL-knockout mice and an effect on improvement in plasma triglycerides. However, triglycerides in liver were increased and there was an unresolved issue of whether there was a direct relationship between the two compartments. There were also some effects on inflammation as measured by circulating cytokines. When analyzing gut microbiota, his data indicated that dysbiosis was resistant to change, but there was an increase in gut microbes that have been positively associated with metabolic health.

Diana Taft from UC Davis continued on the theme of gut microbiota and described an analysis of samples from infants in a study in Bangladesh. The focus was on antibiotic-resistant strains, a concerning problem worldwide, especially in countries like Bangladesh where antibiotics are still cheap and available without a prescription. Using a sequencing approach, Diana examined seven samples with low numbers of bifidobacterial species and eleven with high numbers. She found a higher number of Enterobacteriaceae species, with up to nine antibiotic resistance genes in samples with lower numbers of bifidobacteria. There were a few bifidobacterial species with low antibiotic resistance.

Steve Frese received the most valued speaker award from the 2016 symposium. He presented an update on his work in developing a commercial product based on cultured Bifidobacterium longum infantis, and results of a trial of infant feeding as a supplement to breastfeeding. The goal was to positively influence gut colonization to avoid any dysbiosis that may affect health. The supplement resulted in a 10–100-fold increase in Bifidobacteria longum in the stool samples from the babies and a significant reduction in unfavorable bacterial species over the first year of life. There was a notable decrease in stool pH associated with metabolic changes related to gut microbiota composition. This was associated with anecdotal evidence of reduced defecation frequency, more firm stools, and mothers reported more “settled” babies.

Vanessa Dunne-Castagna studies infant gut microbiota and is interested in the protective effects of immunoglobulin A. The secreted form of IgA (sIgA) is found in breastmilk early in lactation, and Vanessa examined its role in gut colonization. She used a model of gut epithelial cell binding to test the effect of coating bacteria with sIgA. The coating did indeed increase binding of the bacteria to the intestinal cells and, which could provide a protective effect for colonizing bacteria.

David Dallas studied a series of samples from premature infant gastrointestinal tract. The preterm infant gut is immature and unable to produce an appropriate digestive microenvironment, so in this study, samples were analyzed for protein digestion and peptide composition. Peptides are first released within milk as a result of intrinsic proteases, but digestive enzymes are essential for nutrition and potentially for bioactivity directed towards infant development.

Søren Nielsen from Aarhus University, in collaboration with the Dallas lab, described the development of an online tool to search peptide sequences for known bioactivity. The tool draws on 994 database entries and 294 research articles with 606 known peptides. Many of these milk peptides (327) are inhibitors of angiotensin-converting enzyme. The tool provides an individual or file upload facility to search the database and return matches, either as exact or embedded sequences. The analysis is fast and can also provide additional data from public domain protein databases.

Vivi Gregersen, also from Aarhus University, has been quantifying specific milk proteins in dairy herds with an interest in heritability and the potential for selective breeding. There was reasonable heritability for osteopontin, but low values for beta-casein and lactalbumin. Expression analysis suggested a relationship between protein levels and osteopontin or a prolactin effect.

Peter Williamson, the author of this article, presented data from bioactive protein and peptide analysis of a processed whey stream. Following initial work to show that whey proteins have a marked effect on gut development in a mouse model, and a significant effect in gut repair following injury, his graduate student established a semi-automated assay for tissue repair and screened 25 whey proteins from a library of recombinants made from bovine mammary gland genes. Three of the proteins were identified in whey along with 57 free peptides. Thirteen of these peptides had predicted bioactivity when analyzed in silico with the milk bioactive peptide database.

Betty van Esch from Utrecht University gave an update on her work looking for mechanisms to explain observations in a childhood cohort that showed an association between cow’s milk consumption (pasteurized vs unpasteurized) with atopic disease. Using a mouse model, she showed data that supported an immunomodulatory effect of milk consumption as measured by T-cell profiles, cytokine profiles, and mast cell activity. This effect was significant in mice fed untreated milk when compared with heat-treated milk. Disassociating bioactive properties of milk following heat treatment will hopefully provide clues to these effects in future studies.

Benoit Lamarche (INAF Univesité Laval) presented an analysis of evidence for the health impact of dairy with a focus on saturated fats. The premise that dietary guidelines assume independent actions of food components was challenged. Data from his own group showed no impact of dairy foods on risk factors for cardiovascular disease. The complexity of the food was shown to influence measurements of plasma biomarkers, so the matrix represented in cheese had a markedly different effect when compared with that of butter. He argued that simple measures of plasma cholesterol or lipid profiles are a poor measure of risk and that more relevant assays should be used, as provided by the example of macrophage cholesterol efflux. The data support an argument for evaluation of foods—not nutrients—in formulating dietary guidelines. The work of Benoit was reinforced by studies presented by Jean-Philippe Drouin-Chartier (INAF Univesité Laval) that focused on the release of nutrients from different cheeses. Harder cheeses significantly slowed the post-prandial levels of triglycerides and apoB-48.

Bruce German presented his latest discoveries and developments in milk lipids. He was driven by the analysis of Nurit Argov-Argaman of lipids in milk fat globules. A key factor in MFG size is phospholipid composition. In lactating women, the size of MFGs can affect mastitis. Bruce was particularly excited to present the discovery of nanostructures formed during the digestion of milk fats. Ben Boyd (Monash University Australia) found a remarkable nanostructure of milk-derived lipids that appears to facilitate both fat-soluble and water-soluble nutrient absorption through a unique three-dimensional arrangement that provides a dual purpose.

Deborah O’Connor (University of Toronto) presented a view from front lines of the neonatal intensive care unit. The extensive experience of herself and colleagues in nursing care for preterm babies provided a compelling argument for advancing studies of nutritional support for these babies. Data were presented to show a decrease in necrotizing enterocolitis when babies are fed breast milk, but effects on neurodevelopment were not measurable. Deborah argued that some very fundamental research would be enormously beneficial. Her most immediate concerns were with nutrient loss in protocols for handling breast milk of maternal or donor origin. She sees a marked loss in folate and vitamin C following freeze thaw and heat treatments, and a surprisingly high loss of lipid in feeding tubes.

Kevin Nicholas (Moansh Univ, Deakin Univ) and Christophe Lefevre (WEHI) gave a comprehensive summary of lactation biology and bioactivity in marsupial milk. Kevin’s group has pioneered a comparative strategy to understand how the altricial young that grow in the pouch of Tammar wallabies utilize milk of different compositions to grow and develop. In the studies described, there was a focus on the development of a mature lung. Kevin and Christophe presented a wealth of data characterizing the factors involved in lung developmental stages based on studies using gene expression, an in vitro lung culture model and cross-fostering experiments. Milk from different stages of lactation assayed in a mouse model of lung development showed that bioactive factors from milk in the early stage of the lactation cycle were most potent. Interestingly, the extracellular matrix of the mammary gland was shown to control milk bioactive composition.

Paul McJarrow (Fonterra New Zealand) presented an analysis of breast milk oligosaccharides in two Asian ethnic groups of women. Overall there were no ethnic differences in breast milk oligosaccharides, with the possible exception of 3’ fucosylated forms when compared with published studies on non-Asian populations, but there were isolated individual differences, particularly in 3’ fucosylated content. This is consistent with a lack of a 1,3-transferase in some people. There were suggestions of differences in sialyllactose content, but it was difficult to distinguish in comparison with historical data.

Carrie-Ellen Briere has recently established a laboratory at the University of Massachusetts and launched a project to study breast milk-derived stem cells. She confirmed the presence of stem cells in her samples and is currently doing characterization studies using flow cytometry and gene expression analysis. She is particularly interested in translating the health-promoting properties of stem cells in applications related to health and well-being of pre-term babies.

As with previous symposia, selected students were strongly supported with generous travel awards to attend the meeting. This year we heard from Andrea Zukowski (University of Ottawa), Randall Robinson (UC Davis), Léa Guinot (Univesité Laval), Ryskaliyeva Alma (INRA, UMR GABI, AgroParis Tech and Univ Paris-Saclay), and Junai Gan (UC Davis). Andrea described her study on the milk of mastitic cows showing variation in exosome phenotype and size, with an update on analysis of a complex miRNA profile in progress. Alma Ryskaliyeva is a graduate student from Kazakhstan working with Patrice Martin in Paris. She introduced the meeting to the camel milk industry and described how the modern methods of genomics have allowed a very productive analysis of camel lactation. Randall Robinson (UC Davis) described the development of a multiplex assay for milk oligosaccharides. The mass spectrometry-based method used accelerates the analysis of complex oligosaccharide mixtures many fold. He demonstrated its utility by analyzing samples from over 600 dairy cow milk samples. Léa Guinot (Univesité Laval) described a laboratory model for studying digestion and analyzed the release of nutrients from cheese matrices. Junai Gan (UC Davis) described her efforts to unite a team of young researchers in a project focused on milk bioactive peptide discovery. So far the work team has identified 85 peptides for further analysis.

Once again, it was an informative and diverse meeting. See you all next year!

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